NIH PubMed latest 50 research articles on Alzheimer's

Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice.

Demars M, Hu YS, Gadadhar A, Lazarov O

Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice.

J Neurosci Res. 2010 Mar 5;

Authors: Demars M, Hu YS, Gadadhar A, Lazarov O

Formation of new neurons in the adult brain takes place in the subventricular zone and in the subgranule layer of the dentate gyrus throughout life. Neurogenesis is thought to play a role in hippocampus- and olfaction-dependent learning and memory. However, whether impairments in neurogenesis take place in learning and memory disorders, such as Alzheimer's disease, is yet to be established. Importantly, it remains to be elucidated whether neurogenic impairments play a role in the course of the disease or are the result of extensive neuropathology. We now report that transgenic mice harboring familial Alzheimer's disease-linked mutant APPswe/PS1DeltaE9 exhibit severe impairments in neurogenesis that are evident as early as 2 months of age. These mice exhibit a significant reduction in the proliferation of neural progenitor cells and their neuronal differentiation. Interestingly, levels of hyperphosphorylated tau, the cytotoxic precursor of the Alzheimer's disease hallmark neurofibrillary tangles, are particularly high in the neurogenic niches. Isolation of neural progenitor cells in culture reveals that APPswe/PS1DeltaE9-expressing neurospheres exhibit impaired proliferation and tau hyperphosphorylation compared with wildtype neurospheres isolated from nontransgenic littermates. This study suggests that impaired neurogenesis is an early critical event in the course of Alzheimer's disease that may underlie memory impairments, at least in part, and exacerbate neuronal vulnerability in the hippocampal formation and olfaction circuits. Furthermore, impaired neurogenesis is the result of both intrinsic pathology in neural progenitor cells and extrinsic neuropathology in the neurogenic niches. Finally, hyperphosphorylation of the microtubule-associated protein tau, a critical player in cell proliferation, neuronal maturation, and axonal transport, is a major contributor to impaired neurogenesis in Alzheimer's disease. (c) 2010 Wiley-Liss, Inc.

PMID: 20209626 [PubMed - as supplied by publisher]

Genetic Variability in CLU and Its Association with Alzheimer's Disease.

Genetic Variability in CLU and Its Association with Alzheimer's Disease.

PLoS One. 2010;5(3):e9510

Authors: Guerreiro RJ, Beck J, Gibbs JR, Santana I, Rossor MN, Schott JM, Nalls MA, Ribeiro H, Santiago B, Fox NC, Oliveira C, Collinge J, Mead S, Singleton A, Hardy J

BACKGROUND: Recently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU. METHODOLOGY/PRINCIPAL FINDINGS: To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD. CONCLUSIONS/SIGNIFICANCE: We conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein.

PMID: 20209083 [PubMed - as supplied by publisher]

The Alzheimer's Disease-Associated Amyloid beta-Protein Is an Antimicrobial Peptide.

The Alzheimer's Disease-Associated Amyloid beta-Protein Is an Antimicrobial Peptide.

PLoS One. 2010;5(3):e9505

Authors: Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD

BACKGROUND: The amyloid beta-protein (Abeta) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Abeta is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Abeta has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide data supporting an in vivo function for Abeta as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Abeta and LL-37, an archetypical human AMP. Findings reveal that Abeta exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Abeta levels. Consistent with Abeta-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Abeta antibodies. CONCLUSIONS/SIGNIFICANCE: Our findings suggest Abeta is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Abeta-mediated pathology and has important implications for ongoing and future AD treatment strategies.

PMID: 20209079 [PubMed - as supplied by publisher]

Polymorphisms in the Human Apolipoprotein E Receptor 2 Gene in Japanese Sporadic Alzheimer's Disease Patients.

Polymorphisms in the Human Apolipoprotein E Receptor 2 Gene in Japanese Sporadic Alzheimer's Disease Patients.

Biosci Biotechnol Biochem. 2010 Mar 7;

Authors: Hosoda A, Inoue T, Mao CC, Jeong YH, Yamagishi A, Ye M, Yamamoto T, Kim DH, Saeki S

Apolipoprotein E (apoE) polymorphism is associated with onset of Alzheimer's disease (AD). We found seven polymorphisms in apoE receptor 2 (ApoER2), an apoE-binding receptor, in Japanese sporadic AD patients, but no association of ApoER2 polymorphisms with AD. We consider that the functions of ApoER2 in the brain may be compensated for by those of other apoE-binding receptors such as VLDL receptor.

PMID: 20208369 [PubMed - as supplied by publisher]

Using the life course perspective to study the entry into the illness trajectory: The perspective of caregivers of people with Alzheimer's disease.

Carpentier N, Bernard P, Grenier A, Guberman N

Using the life course perspective to study the entry into the illness trajectory: The perspective of caregivers of people with Alzheimer's disease.

Soc Sci Med. 2010 Feb 19;

Authors: Carpentier N, Bernard P, Grenier A, Guberman N

The research community is showing increasing interest in the analysis of the care trajectory of people with chronic health problems, especially dementias such as Alzheimer's disease. However, despite this interest, there is little research on the initial phases of the care trajectory. The fact that the first symptoms of dementia are generally noticed by those surrounding the elderly person suggests that the recognition of the disease is intimately linked to interactions not only amongst family members but also amongst friends, neighbours and health professionals. This study focuses on the period beginning with the first manifestations of cognitive difficulties and ending with the diagnosis of Alzheimer-type dementia. Interviews with 60 caregivers in Montreal, Canada were used to reconstruct how older people with Alzheimer-type dementia enter into the care trajectory. Our methods consisted of the analysis of social networks, social dynamics and action sequences. Our findings are presented in the form of a typology comprised of 5 pathways of entries into the care trajectory that are structured around the following four principles of the Life Course Perspective: family history, linked lives, human agency and organisational effects. We believe that analyses of the initial phases of the care trajectory, such as this one, are essential for the application of effective early detection and intervention policies. They are also central to informing future studies that seek to understand the care experience in its entirety.

PMID: 20207459 [PubMed - as supplied by publisher]

Purine derivatives as potent gamma-secretase modulators.

Purine derivatives as potent gamma-secretase modulators.

Bioorg Med Chem Lett. 2010 Feb 6;

Authors: Rivkin A, Ahearn SP, Chichetti SM, Hamblett CL, Garcia Y, Martinez M, Hubbs JL, Reutershan MH, Daniels MH, Siliphaivanh P, Otte KM, Li C, Rosenau A, Surdi LM, Jung J, Hughes BL, Crispino JL, Nikov GN, Middleton RE, Moxham CM, Szewczak AA, Shah S, Moy LY, Kenific CM, Tanga F, Cruz JC, Andrade P, Angagaw MH, Shomer NH, Miller T, Munoz B, Shearman MS

The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.

PMID: 20207146 [PubMed - as supplied by publisher]

Midregional Proenkephalin A and N-terminal Protachykinin A are decreased in the cerebrospinal fluid of patients with dementia disorders and acute neuroinflammation.

Midregional Proenkephalin A and N-terminal Protachykinin A are decreased in the cerebrospinal fluid of patients with dementia disorders and acute neuroinflammation.

J Neuroimmunol. 2010 Mar 4;

Authors: Ernst A, Buerger K, Hartmann O, Dodel R, Noelker C, Sommer N, Schwarz M, Köhrle J, Bergmann A, Hampel H

Midregional Proenkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) are stable fragments of the precursor peptides for enkephalins and substance P, respectively. We measured MR-PENK A and NT-PTA concentrations by sensitive chemiluminescence immunoassays in cerebrospinal fluid (CSF) of 19 neurologically healthy controls (NHC), 28 patients with other neurologic disorders (OND), 70 patients with dementia disorders (38 Alzheimer's disease [AD], 8 dementia with Lewy bodies [DLB], 12 frontotemporal dementia [FTD], and 12 patients with vascular dementia [VD]), and 16 patients with acute neuroinflammation (AN). Median concentrations of NT-PTA were decreased in all patient groups compared to NHC showing significant differences between patients with NHC and AN (p<0.001), OND and AN (p<0.001), FTD and AN (p<0.01) and pAD and AN (p<0.05). Median MR-PENK A levels were lower in patients with OND, dementia disorders (including AD, FTD, DLB and VD) and AN compared to NHC subjects, although this differences did not reach statistical significance (p>0.05). A maximum difference of both proneuropeptide fragments was found between NHC subjects and patients with AN, with a more than 2fold decrease in median NT-PTA and a 1.5fold decrease in median MR-PENK A levels. Concentrations of both proneuropeptide fragments were positively correlated in all patients (r=0.77, p<0.001). Our results indicate alterations of the cerebral PENK A- and PTA-system in both, dementia and acute neuroinflammatory disorders. These neuropeptide systems seem to be highly correlated in healthy and pathological status.

PMID: 20207019 [PubMed - as supplied by publisher]

Detection by voxel-wise statistical analysis of significant changes in regional cerebral glucose uptake in an APP/PS1 transgenic mouse model of Alzheimer's disease.

Dubois A, Hérard AS, Delatour B, Hantraye P, Bonvento G, Dhenain M, Delzescaux T

Detection by voxel-wise statistical analysis of significant changes in regional cerebral glucose uptake in an APP/PS1 transgenic mouse model of Alzheimer's disease.

Neuroimage. 2010 Mar 3;

Authors: Dubois A, Hérard AS, Delatour B, Hantraye P, Bonvento G, Dhenain M, Delzescaux T

Biomarkers and technologies similar to those used in humans are essential for the follow-up of Alzheimer's disease (AD) animal models, particularly for the clarification of mechanisms and the screening and validation of new candidate treatments. In humans, changes in brain metabolism can be detected by 1-deoxy-2-[(18)F] fluoro-D-glucose PET (FDG-PET) and assessed in a user- independent manner with dedicated software, such as Statistical Parametric Mapping (SPM). FDG-PET can be carried out in small animals, but its resolution is low as compared to the size of rodent brain structures. In mouse models of AD, changes in cerebral glucose utilization are usually detected by [(14)C]-2-deoxyglucose (2DG) autoradiography, but this requires prior manual outlining of regions of interest (ROI) on selected sections. Here, we evaluate the feasibility of applying the SPM method to 3D autoradiographic data sets mapping brain metabolic activity in a transgenic mouse model of AD. We report the preliminary results obtained with 4 APP/PS1 (64+/-1weeks) and 3 PS1 (65+/-2weeks) mice. We also describe new procedures for the acquisition and use of "blockface" photographs and provide the first demonstration of their value for the 3D reconstruction and spatial normalization of post mortem mouse brain volumes. Despite this limited sample size, our results appear to be meaningful, consistent, and more comprehensive than findings from previously published studies based on conventional ROI-based methods. The establishment of statistical significance at the voxel level, rather than with a user-defined ROI, makes it possible to detect more reliably subtle differences in geometrically complex regions, such as the hippocampus. Our approach is generic and could be easily applied to other biomarkers and extended to other species and applications.

PMID: 20206704 [PubMed - as supplied by publisher]

Thinking outside the box about COX-1 in Alzheimer's Disease.

Frautschy SA

Thinking outside the box about COX-1 in Alzheimer's Disease.

Neurobiol Dis. 2010 Mar 2;

Authors: Frautschy SA

This article from Coma and colleagues shows that a salicylic acid derivative Triflusal, a platelet aggregation inhibitor and irreversible inhibitor of COX-1, can correct defects in axonal curvature and cognition in an AD transgenic mouse model (Tg2576) (Coma et al., 2010). Here we discuss the controversy over the role of COX-1 in AD, which has not been considered carefully in part due to the presumed adverse gastrointestinal effects of COX-1 antagonism. However, recent clinical data from this group as well as other groups challenges this assumption that COX-1 antagonism will be associated with side effects. Most importantly this article raises critical questions about the role of COX-1, versus COX-2 versus both in Abeta pathogenesis. The animal model data in this article as well as the recently published trial data suggest that COX-1 may play an important role in early pathogenesis and should not be ignored as a potential target for early intervention.

PMID: 20206264 [PubMed - as supplied by publisher]

Exploring new indications for statins beyond atherosclerosis: Successes and setbacks.

Waters DD

Exploring new indications for statins beyond atherosclerosis: Successes and setbacks.

J Cardiol. 2010 Mar;55(2):155-162

Authors: Waters DD

Statins have been shown to reduce cardiovascular events across a broad spectrum of patients at risk, irrespective of baseline LDL-cholesterol levels. In a meta-analysis of 14 statin trials involving more than 90,000 participants, statin therapy reduced the 5-year incidence of cardiovascular events by about 20% for each mmol/L of LDL-cholesterol reduction. The results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study suggest that the degree of reduction in Japanese subjects may be greater than this for the same degree of LDL-cholesterol reduction. Given the success of statins in preventing cardiovascular events, it is not surprising that they have been tested in a variety of related conditions, three of which are discussed in this article. Heart failure is characterized by inflammation, endothelial dysfunction and neurohumeral activation, conditions that are ameliorated by statin therapy. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) showed no significant benefit of rosuvastatin upon the primary endpoint, cardiovascular death, myocardial infarction and stroke. However, subgroups identified by the biomarkers plasma amino-terminal pro-brain natriuretic and C-reactive protein showed a reduction in events. Aortic stenosis and atherosclerosis share common risk factors, including hypertension and hypercholesterolemia. Although non-randomized cohort studies have suggested that statins slow the progression of aortic stenosis, this was not shown in either of the two randomized placebo-controlled trials testing this hypothesis. Similarly, Alzheimer's disease shares many risk factors with atherosclerosis, and several observational studies have reported a lower risk of developing this condition in patients taking statins. However, two recently completed clinical trials indicate that neither atorvastatin nor simvastatin slow the progression of early Alzheimer's disease. In conclusion, although statins are effective, established therapy for the prevention of vascular events in patients at risk, they have as yet not proven to be successful for these newer indications.

PMID: 20206067 [PubMed - as supplied by publisher]

A nuclear factor-binding domain in the 5'-untranslated region of the amyloid precursor protein promoter: Implications for the regulation of gene expression.

Vostrov AA, Taheny MJ, Izkhakov N, Quitschke WW

A nuclear factor-binding domain in the 5'-untranslated region of the amyloid precursor protein promoter: Implications for the regulation of gene expression.

BMC Res Notes. 2010;3(1):4

Authors: Vostrov AA, Taheny MJ, Izkhakov N, Quitschke WW

ABSTRACT: BACKGROUND: The extracellular deposition of aggregated amyloid beta-protein is a neuropathological manifestation of Alzheimer disease and Down syndrome. The Amyloid beta-protein is derived from a group of larger differentially spliced proteins, the amyloid protein precursors (APP). Data suggests that the level of APP gene expression could contribute to the pathological processes leading to amyloid depositions. FINDINGS: The 5' untranslated region (UTR) of the APP gene, encompassing 147 base pairs between the transcriptional (+1) and the translational start site, was examined for its role in APP expression. Deletions close to the transcriptional start site reduced expression from the APP promoter in part by transcriptional mechanisms. However, deletions between position +50 and +104 had no effect on transcriptional activity while significantly reducing overall expression from the promoter. A nuclear factor-binding domain designated as DAPB was identified between position +72 and +115 of the 5'-APP-UTR. The binding-recognition sequence was localized between position +96 and +105. The same mutations that eliminated factor-binding also reduced expression from the APP promoter while having no effect on in vitro transcription or the RNA levels transcribed from transfected constructs. CONCLUSIONS: A nuclear factor-binding domain designated as DAPB was identified in the 5'-UTR of the APP gene. Elimination of factor-binding correlated with an overall decline in expression from the APP promoter while in vitro transcription and the total amount of in vivo transcribed RNA remained unaffected. This suggests that the binding-factor may have a function in post-transcriptional regulation, including nuclear export of mRNA.

PMID: 20205906 [PubMed - as supplied by publisher]

Curcumin, inflammation, ageing and age-related diseases.

Sikora E, Scapagnini G, Barbagallo M

Curcumin, inflammation, ageing and age-related diseases.

Immun Ageing. 2010;7(1):1

Authors: Sikora E, Scapagnini G, Barbagallo M

ABSTRACT: A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy between April 7 and 8th 2009. Here the lecture by Sikora with some input from the chairpersons Scapagnini and Barbagallo is summarized. Ageing is manifested by the decreasing health status and increasing probability to acquire age-related disease such as cancer, Alzheimer's disease, atherosclerosis, metabolic disorders and others. They are likely caused by low grade inflammation driven by oxygen stress and manifested by the increased level of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha, encoded by genes activated by the transcription factor NF-kappaB. It is believed that ageing is plastic and can be slowed down by caloric restriction as well as by some nutraceuticals. Accordingly, slowing down ageing and postponing the onset of age-related diseases might be achieved by blocking the NF-kappaB-dependent inflammation. In this review we consider the possibility of the spice curcumin, a powerful antioxidant and anti-inflammatory agent possibly capable of improving the health status of the elderly.

PMID: 20205886 [PubMed - as supplied by publisher]

Axotomy-induced neurotrophic withdrawal causes the loss of phenotypic differentiation and downregulation of NGF signalling, but not death of septal cholinergic neurons.

Lazo OM, Mauna JC, Pissani CA, Inestrosa NC, Bronfman FC

Axotomy-induced neurotrophic withdrawal causes the loss of phenotypic differentiation and downregulation of NGF signalling, but not death of septal cholinergic neurons.

Mol Neurodegener. 2010;5(1):5

Authors: Lazo OM, Mauna JC, Pissani CA, Inestrosa NC, Bronfman FC

ABSTRACT: BACKGROUND: Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target-derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF) from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease.The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats. RESULTS: We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion. CONCLUSIONS: Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival of neurons. This evidence raises questions about the relationship between transcriptional regulation of the cholinergic phenotype by retrograde-derived trophic signaling and the transcriptional changes experienced when retrograde transport is impaired due to neuropathological conditions.

PMID: 20205865 [PubMed - as supplied by publisher]

Assessment of cognitive status in patients with type 2 diabetes through the mini-mental status examination: a cross-sectional study.

Alencar RC, Cobas RA, Gomes MB

Assessment of cognitive status in patients with type 2 diabetes through the mini-mental status examination: a cross-sectional study.

Diabetol Metab Syndr. 2010;2(1):10

Authors: Alencar RC, Cobas RA, Gomes MB

ABSTRACT: BACKGROUND: Diabetes is considered an independent risk factor for cognitive impairment and some studies observed through neuropsychological tests that cognitive disfunction affects both elderly and younger patients with diabetes. The aims of this study were to evaluate the cognitive status of outpatients with type 2 diabetes and to evaluate factors associated with impaired function. METHODS: A cross-sectional study was conducted in a group of type 2 diabetic outpatients. They were asked to undergo the Mini-Mental State Examination (MMSE) during routine ambulatory visits between April 2006 and January 2007, with the highest pontuation of the test being 30 points. Patients were classified as having possible dementia according to years of study. Exclusion criteria were blindness, illiterately, stroke, Alzheimer disease and psychiatric disorder. Results are presented as median (interquartile range) or mean +/- SD. RESULTS: The study group was composed of 346 type 2 diabetic outpatients (216 females), aged 58,6 +/- 12,1 years and with duration of diabetes of 12,3 +/- 9,1 years. Hypertension was present in 77,2%. The total MMSE score achieved was 26 points (16 - 30) and was correlated with years of study (R2 = 0,39, p < 0,001) and 'per capita' income (R2 = 0,22, p < 0,0001) and duration of diabetes (R2 = - 0,13, p = 0,01). Patients who needed help to take their medications obtained worst performance in the MMSE (23,16 +/- 3,55 vs 25,7 +/- 2,84, p < 0,01) and were more likely to present possible dementia (p < 0,01). Forty two subjects (12.1%) had diagnosis of possible dementia and this was also associated with years of study (p = 0,045). No association was observed between possible dementia and total MMSE scores with A1C levels. CONCLUSIONS: We conclude that patients with type 2 diabetes should be regularly evaluated for their cognitive function, because duration of disease could be associated with decline in cognition. The early implementation of mini mental which is a simple method of execution can be done to detect early stages of dementia. This test could be an important tool to access the ability of patient to understand their disease and treatment.

PMID: 20205826 [PubMed - as supplied by publisher]

Amyloid-beta-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Abeta peptide. Implications for the pathogenesis of Alzheimer's disease.

Dinamarca MC, Sagal JP, Quintanilla RA, Godoy JA, Arrázola MS, Inestrosa NC

Amyloid-beta-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Abeta peptide. Implications for the pathogenesis of Alzheimer's disease.

Mol Neurodegener. 2010;5(1):4

Authors: Dinamarca MC, Sagal JP, Quintanilla RA, Godoy JA, Arrázola MS, Inestrosa NC

ABSTRACT: The presence of amyloid-beta (Abeta) deposits in selected brain regions is a hallmark of Alzheimer's disease (AD). The amyloid deposits have "chaperone molecules" which play critical roles in amyloid formation and toxicity. We report here that treatment of rat hippocampal neurons with Abeta-acetylcholinesterase (Abeta-AChE) complexes induced neurite network dystrophia and apoptosis. Moreover, the Abeta-AChE complexes induced a sustained increase in intracellular Ca2+ as well as a loss of mitochondrial membrane potential. The Abeta-AChE oligomers complex also induced higher alteration of Ca2+ homeostasis compared with Abeta-AChE fibrillar complexes. These alterations in calcium homeostasis were reversed when the neurons were treated previously with lithium, a GSK-3beta inhibitor; Wnt-7a ligand, an activator for Wnt Pathway; and an N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801), demonstrating protective roles for activation of the Wnt signaling pathway as well as for NMDA-receptor inhibition. Our results indicate that the Abeta-AChE complexes enhance Abeta-dependent deregulation of intracellular Ca2+ as well as mitochondrial dysfunction in hippocampal neurons, triggering an enhanced damage than Abeta alone. From a therapeutic point of view, activation of the Wnt signaling pathway, as well as NMDAR inhibition may be important factors to protect neurons under Abeta-AChE attack.

PMID: 20205793 [PubMed - as supplied by publisher]

Extensive proteomic screening identifies the obesity-related NYGGF4 protein as a novel LRP1-interactor, showing reduced expression in early Alzheimer's disease.

Extensive proteomic screening identifies the obesity-related NYGGF4 protein as a novel LRP1-interactor, showing reduced expression in early Alzheimer's disease.

Mol Neurodegener. 2010;5(1):1

Authors: Kajiwara Y, Franciosi S, Takahashi N, Krug L, Schmeidler J, Taddei K, Haroutunian V, Fried U, Ehrlich M, Martins RN, Gandy S, Buxbaum JD

ABSTRACT: BACKGROUND: The low-density lipoprotein receptor related protein 1 (LRP1) has been implicated in Alzheimer's disease (AD) but its signalling has not been fully evaluated. There is good evidence that the cytoplasmic domain of LRP1 is involved in protein-protein interactions, important in the cell biology of LRP1. RESULTS: We carried out three yeast two-hybrid screens to identify proteins that interact with the cytoplasmic domain of LRP1. The screens included both conventional screens as well as a novel, split-ubiquitin-based screen in which an LRP1 construct was expressed and screened as a transmembrane protein. The split-ubiquitin screen was validated in a screen using full-length amyloid protein precursor (APP), which successfully identified FE65 and FE65L2, as well as novel interactors (Rab3a, Napg, and ubiquitin b). Using both a conventional screen as well as the split-ubiquitin screen, we identified NYGGF4 as a novel LRP1 interactor. The interaction between LRP1 and NYGGF4 was validated using two-hybrid assays, coprecipitation and colocalization in mammalian cells. Mutation analysis demonstrated a specific interaction of NYGGF4 with an NPXY motif that required an intact tyrosine residue. Interestingly, while we confirmed that other LRP1 interactors we identified, including JIP1B and EB-1, were also able to bind to APP, NYGGF4 was unique in that it showed specific binding with LRP1. Expression of NYGGF4 decreased significantly in patients with AD as compared to age-matched controls, and showed decreasing expression with AD disease progression. Examination of Nyggf4 expression in mice with different alleles of the human APOE4 gene showed significant differences in Nyggf4 expression. CONCLUSIONS: These results implicate NYGGF4 as a novel and specific interactor of LRP1. Decreased expression of LRP1 and NYGGF4 over disease, evident with the presence of even moderate numbers of neuritic plaques, suggests that LRP1-NYGGF4 is a system altered early in disease. Genetic and functional studies have implicated both LRP1 and NYGGF4 in obesity and cardiovascular disease and the physical association of these proteins may reflect a common mechanism. This is particularly interesting in light of the dual role of ApoE in both cardiovascular risk and AD. The results support further studies on the functional relationship between NYGGF4 and LRP1.

PMID: 20205790 [PubMed - as supplied by publisher]

Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

Cerpa W, Farías GG, Godoy JA, Fuenzalida M, Bonansco C, Inestrosa NC

Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

Mol Neurodegener. 2010;5(1):3

Authors: Cerpa W, Farías GG, Godoy JA, Fuenzalida M, Bonansco C, Inestrosa NC

ABSTRACT: BACKGROUND: Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation. RESULTS: We report here that the Wnt signaling activation prevents the synaptic damage triggered by Abeta oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components. CONCLUSION: These results indicate that post-synaptic damage induced by Abeta oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

PMID: 20205789 [PubMed - as supplied by publisher]

The Pulse of Drug Development for Alzheimer's Disease.

Rafii MS

The Pulse of Drug Development for Alzheimer's Disease.

Rev Recent Clin Trials. 2010 Jan 1;5(1):57-62

Authors: Rafii MS

Therapies that are believed to target the underlying mechanisms of Alzheimer's disease have now reached human clinical trials, with the number of agents in late stage development having increased dramatically in recent years. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the formation of neurofibrillary tangles of paired helical filaments, also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, the current status of Alzheimer's Disease therapies under study is discussed, including the scientific basis for each strategy.

PMID: 20205688 [PubMed - as supplied by publisher]

Properties of CA3 Dendritic Excrescences in Alzheimer's Disease.

Tsamis IK, Mytilinaios GD, Njau NS, Fotiou FD, Glaftsi S, Costa V, Baloyannis JS

Properties of CA3 Dendritic Excrescences in Alzheimer's Disease.

Curr Alzheimer Res. 2010 Feb 1;7(1):84-90

Authors: Tsamis IK, Mytilinaios GD, Njau NS, Fotiou FD, Glaftsi S, Costa V, Baloyannis JS

CA3 pyramidal neurons and hilar mossy neurons possess large and branched dendritic spines, named thorny excrescences. Studies on experimental animals have shown great morphologic adaptation of the excrescences and the whole dendritic tree of CA3 pyramidal neurons in changes of environmental conditions. However, the available data about the excrescences in human brain is short and insufficient about their properties in Alzheimer's disease. In the present study, these dendritic structures were studied and compared in CA3 area of hippocampus in patients suffered from Alzheimer's disease, age matched controls and young individuals. Golgi impregnated material under light microscopy was used for the description of the structural characteristics of the excrescences. Morphometric estimation of their density on the apical and basilar dendritic tree and their average length revealed reduced density and significantly increased size in Alzheimer's disease patients. The mean density of the excrescences on the apical dendritic tree of the patients compared to age matched controls is reduced 32.8% (p<0.001), while the mean number of long excrescences (longer than 5microm) is increased 32.6% (p<0.05). On the basilar dendritic tree, the reduction in density is 26.3% (p<0.05) and the increase in the number of long excrescences is 23.3% (p>0.05). These enlarged thorny excrescences can be even longer than 10microm, appearing as "giant spines". The increased size of the excrescences is considered as a remodeling procedure (compensative mechanism) of the CA3 pyramidal neurons for the balancing of the reduction in the spinal density.

PMID: 20205674 [PubMed - as supplied by publisher]

Effects of Cholinesterase Inhibitors on the Activities and Protein Levels of Cholinesterases in the Cerebrospinal Fluid of Patients with Alzheimer's Disease: A Review of Recent Clinical Studies.

Darreh-Shori T, Soininen H

Effects of Cholinesterase Inhibitors on the Activities and Protein Levels of Cholinesterases in the Cerebrospinal Fluid of Patients with Alzheimer's Disease: A Review of Recent Clinical Studies.

Curr Alzheimer Res. 2010 Feb 1;7(1):67-73

Authors: Darreh-Shori T, Soininen H

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline associated with a deficit in cholinergic function. Inhibitors of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE), such as donepezil, galantamine or rivastigmine, are widely prescribed as symptomatic treatments for AD. These agents exhibit a wide variation in their pharmacological properties. Here we review clinical data from 1998 to 2009 investigating the effect of different cholinesterase inhibitor treatments on the levels and activities of cholinesterases in the cerebrospinal fluid (CSF) of AD patients. These studies suggest that treatment with rapidly-reversible cholinesterase inhibitors (e.g. donepezil, galantamine, tacrine) are associated with marked and significant upregulation of AChE activities and protein levels in the CSF of AD patients. In contrast, pseudo-irreversible cholinesterase inhibition (e.g. rivastigmine) is associated with a significant decrease in both CSF AChE and BuChE activities, with no upregulation of CSF protein levels. Additionally, donepezil is associated with a decrease in the level of the AChE-R isoform relative to the synaptic AChE-S isoform, whereas rivastigmine seems to increase this ratio. These findings suggest that these agents exert different effects on CSF cholinesterases. The clinical effects of these pharmacological differences are yet to be fully established.

PMID: 20205672 [PubMed - as supplied by publisher]

High PIB Retention in Alzheimer's Disease is an Early Event with Complex Relationship with CSF Biomarkers and Functional Parameters.

Forsberg A, Almkvist O, Engler H, Wall A, Långström B, Nordberg A

High PIB Retention in Alzheimer's Disease is an Early Event with Complex Relationship with CSF Biomarkers and Functional Parameters.

Curr Alzheimer Res. 2010 Feb 1;7(1):56-66

Authors: Forsberg A, Almkvist O, Engler H, Wall A, Långström B, Nordberg A

Background:New in vivo amyloid PET imaging tracers, such as (11)C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how (11)C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers. Method: Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer (11)C-PIB, (18)F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (Abeta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs). Results: Pooled data from AD and MCI patients showed strong correlations between (11)C-PIB retention, levels of CSF biomarkers (especially Abeta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between (11)C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between (11)C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions. Conclusions: A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. (11)C-PIB PET and CSF Abeta(42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

PMID: 20205671 [PubMed - as supplied by publisher]

Nicotinic Acetylcholine Receptor Interaction with beta-Amyloid: Molecular, Cellular, and Physiological Consequences.

Parri RH, Dineley TK

Nicotinic Acetylcholine Receptor Interaction with beta-Amyloid: Molecular, Cellular, and Physiological Consequences.

Curr Alzheimer Res. 2010 Feb 1;7(1):27-39

Authors: Parri RH, Dineley TK

Elevated amyloid-beta peptide (Abeta) and loss of nicotinic acetylcholine receptors (nAChRs) stand prominently in the etiology of Alzheimer's disease (AD). Since the discovery of an Abeta - nAChR interaction, much effort has been expended to characterize the consequences of high versus low concentrations of Abeta on nAChRs. This review will discuss current knowledge on the subject at the molecular, cellular, and physiological levels with particular emphasis on understanding how Abeta - nAChR interaction may contribute to normal physiological processes as well as the etiology of AD.

PMID: 20205670 [PubMed - as supplied by publisher]

Familial Alzheimer's Disease Mutations in Presenilin 1 Do Not Alter Levels of the Secreted Amyloid-beta Protein Precursor Generated by beta-Secretase Cleavage.

Zhang C, Browne A, Kim DY, Tanzi RE

Familial Alzheimer's Disease Mutations in Presenilin 1 Do Not Alter Levels of the Secreted Amyloid-beta Protein Precursor Generated by beta-Secretase Cleavage.

Curr Alzheimer Res. 2010 Feb 1;7(1):21-26

Authors: Zhang C, Browne A, Kim DY, Tanzi RE

Alzheimer's disease (AD) is an insidious and progressive disease with a genetically complex and heterogenous etiology. More than 200 fully penetrant mutations in the amyloid beta-protein precursor (APP), presenilin 1 (or PSEN1), and presenilin 2 (PSEN2) have been linked to early-onset familial AD (FAD). 177 PSEN1 FAD mutations have been identified so far and account for more than approximately 80% of all FAD mutations. All PSEN1 FAD mutations can increase the Abeta42:Abeta40 ratio with seemingly different and incompletely understood mechanisms. A recent study has shown that the 286 amino acid N-terminal fragment of APP (N-APP), a proteolytic product of beta-secretase-derived secreted form of APP (sAPPbeta), could bind the death receptor, DR6, and lead to neurodegeneration. Here we asked whether PSEN1 FAD mutations lead to neurodegeneration by modulating sAPPbeta levels. All four different PSEN1 FAD mutations tested (in three mammalian cell lines) did not alter sAPPbeta levels. Therefore PS1 mutations do not appear to contribute to AD pathogenesis via altered production of sAPPbeta.

PMID: 20205669 [PubMed - as supplied by publisher]

Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) Patients are Characterized by Increased BDNF Serum Levels.

Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) Patients are Characterized by Increased BDNF Serum Levels.

Curr Alzheimer Res. 2010 Feb 1;7(1):15-20

Authors: Angelucci F, Spalletta G, di Iulio F, Ciaramella A, Salani F, Colantoni L, Varsi AE, Gianni W, Sancesario G, Caltagirone C, Bossù P

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline with loss of memory. In the last years there has been a great interest on the early phases of AD, trying to identify the pathogenic mechanisms of AD and define early treatment modalities. In particular, Mild Cognitive Impairment (MCI) is attractive because it represents a transitional state between normal aging and dementia, although not all MCI patients automatically convert to AD. The neurotrophin brain-derived neurotrophic factor (BDNF) is critical for survival and function of neurons that degenerate in AD and represents a potential neuroprotective agent. However, opposite data on serum levels of BDNF have been reported in AD patients, probably reflecting differences in patient recruitment and stage of the disease. Thus, in this study we measured BDNF serum levels in AD patients (with different degree of severity), MCI patients and healthy subjects. We found that serum BNDF levels were significantly increased in MCI and AD patients when compared to healthy subjects and this increase in AD patients was neither dependent on illness severity, nor on treatment with Acetylcholinesterase inhibitors and/or antidepressant medications. Our findings indicate that BDNF serum levels increase in MCI and AD patients, supporting the hypothesis of an upregulation of BDNF in both preclinical phase of dementia (MCI) and clinical stages of AD. Other studies are necessary to establish a direct link between BDNF peripheral levels and AD longitudinal course, as well as the role of other factors, such as blood cell activation, in determining these events.

PMID: 20205668 [PubMed - as supplied by publisher]

Alzheimer's Disease and Retinal Neurodegeneration.

Guo L, Duggan J, Cordeiro MF

Alzheimer's Disease and Retinal Neurodegeneration.

Curr Alzheimer Res. 2010 Feb 1;7(1):3-14

Authors: Guo L, Duggan J, Cordeiro MF

Alzheimer's disease (AD) is the major cause of dementia in the world. Although the entorhinal cortex and hippocampal complex are best known as the sites of early pathology in AD, increasing evidence shows that the eye, particularly the retina, is also affected. The AD-related changes in the retina are associated with degeneration and loss of neurons, reduction of the retinal nerve fibres, increase in optic disc cupping, retinal vascular tortusity and thinning, and visual functional impairment. Given the fact that evaluating pathologic changes in the brain during life has always been an indirect process, largely shielded from view by the barrier of the skull, the eye can be used as a window into diseases of the brain. Using modern techniques, the changes in the retina can be visualized in real-time. In addition to the changes in the eyes of AD patients, similar mechanisms of neurodegeneration in the brain have also been demonstrated in the eye. Targeting AD-liked changes in the retina has been recently shown to be effective in the reduction of retinal neuronal degeneration and loss in eye diseases. This review will cover recent findings on retinal degeneration in AD, pathological similarities between AD and eye diseases, and highlight the potential of modern technologies for the detection of prospective biomarkers in the eye in early AD.

PMID: 20205667 [PubMed - as supplied by publisher]

N-(tert)-Butyloxycarbonyl)-beta,beta-Cyclopentyl-Cysteine (Acetamidomethyl)-Methyl Ester for Synthesis of Novel Peptidomimetic Derivatives.

N-(tert)-Butyloxycarbonyl)-beta,beta-Cyclopentyl-Cysteine (Acetamidomethyl)-Methyl Ester for Synthesis of Novel Peptidomimetic Derivatives.

Protein Pept Lett. 2010 Mar 6;

Authors: Mollica A, Feliciani F, Stefanucci A, Cacciatore I, Cornacchia C, Torino D, Pinnen F

It has been recently reported that thiol groups could play an important role in the protection of neuronal cells in Alzheimer's disease (AD), prion disease (CJD) and Parkinson's disease (PD). Also bucillamine, that is a pseudo dipeptide possessing a thiol group capable to form an internal disulfide bridge, has relevant scavenger properties used in therapy for the treatment of arthritis. Also furthermore, many sulphur containing compounds show strong chelating properties to heavy metals. Due to the crucial role of thiol groups in a variety of detoxicant biological systems, we report the synthesis of a racemic beta,beta-dialkylsubstituted, fully protected, cysteine derivative as a suitable intermediate in the synthesis of novel biological active peptides.

PMID: 20205656 [PubMed - as supplied by publisher]

Inflammation, Immunity, and Alzheimer's Disease.

Town T

Inflammation, Immunity, and Alzheimer's Disease.

CNS Neurol Disord Drug Targets. 2010 Mar 6;

Authors: Town T

Few topics in the field of Alzheimer's disease (AD) research have brought about the level of excitement and interest as the role of inflammation and immunity in the pathobiology and treatment of the disease. In this special issue of the journal, experts in the field give their views on how inflammatory processes and the immune system intersect- at both etiological and treatment levels- with disease biology. Collectively, nearly three decades of work are covered in this special issue, beginning with the first epidemiologic studies that showed an inverse risk relationship between AD and use of non-steroidal anti-inflammatory drugs, and ending with "immunotherapy" approaches and recent studies examining the roles of innate immune cells including microglia and peripheral mononuclear phagocytes in AD. Despite considerable work in this area, many important questions remain concerning the nature and timing of immune/inflammatory responses in the context of AD, and at what point and how to therapeutically intervene.

PMID: 20205648 [PubMed - as supplied by publisher]

Non-Steroidal Anti-Inflammatory Drugs and Alzheimer's Disease: The Epidemiological Evidence.

Szekely CA, Zandi PP

Non-Steroidal Anti-Inflammatory Drugs and Alzheimer's Disease: The Epidemiological Evidence.

CNS Neurol Disord Drug Targets. 2010 Mar 6;

Authors: Szekely CA, Zandi PP

Alzheimer's disease imposes a significant public health burden that will only worsen as the population ages. Thus, there is considerable motivation to develop effective strategies to treat, or more ideally, prevent the disease. Epidemiologic evidence has suggested that non-steroidal anti-inflammatory drugs (or NSAIDs) may be neuro-protective. However, this evidence is controversial. Observational studies in humans have found that the use of NSAIDs is associated with a lower risk of developing Alzheimer's disease. By contrast, randomized trials have reported that NSAIDs are not effective in treating patients with clinically established disease nor in preventing the onset of dementia among those who are cognitively normal or have mild cognitive impairment. In this article, we review the existing epidemiologic evidence on the relationship between NSAIDs and Alzheimer's disease and discuss several hypotheses to explain the divergent findings.

PMID: 20205647 [PubMed - as supplied by publisher]

Mechanisms of Action of Non-Steroidal Anti-Inflammatory Drugs for the Prevention of Alzheimer's Disease.

Fiala M, Frautschy SA

Mechanisms of Action of Non-Steroidal Anti-Inflammatory Drugs for the Prevention of Alzheimer's Disease.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Fiala M, Frautschy SA

Alzheimer disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDS). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDS cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD patients have failed and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.

PMID: 20205646 [PubMed - as supplied by publisher]

Impact of the CD40-CD40L dyad in Alzheimer's Disease.

Giunta B, Rezai-Zadeh K, Tan J

Impact of the CD40-CD40L dyad in Alzheimer's Disease.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Giunta B, Rezai-Zadeh K, Tan J

As the number of elderly individuals rises, Alzheimer's disease (AD), marked by amyloid-beta deposition, neurofibrillary tangle formation, and low-level neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of membrane-bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD. Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with amyloid-beta immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future.

PMID: 20205645 [PubMed - as supplied by publisher]

Microglia and Inflammation in Alzheimer's Disease.

Mandrekar S, Landreth GE

Microglia and Inflammation in Alzheimer's Disease.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Mandrekar S, Landreth GE

One hundred and fifty years have elapsed since the original discovery of the microglial cell by Virchow. While this cell type has been well studied, the role of microglia in the pathology of many central nervous system diseases still remains enigmatic. It is widely accepted that microglial-mediated inflammation contributes to the progression of Alzheimer's disease (AD); however, the precise mechanisms through which these cells contribute to AD-related inflammation remains to be elucidated. In the AD brain, microglial cells are found in close association with amyloid beta (Abeta) deposits. Histological examination of AD brains as well as cell culture studies have shown that the interaction of microglia with fibrillar Abeta leads to their phenotypic activation. The conversion of these cells into a classically 'activated' phenotype results in production of chemokines, neurotoxic cytokines and reactive oxygen and nitrogen species that are deleterious to the CNS. However, microglia also exert a neuroprotective role through their ability to phagocytose Abeta particles and clear soluble forms of Abeta. These cells have been documented to play integral roles in tissue repair and inflammation, and in recent years it has been appreciated that this cell type is capable of facilitating a more complex response to pathogens by changing their activation status. A variety of new findings indicate that their role in the central nervous system is far more complex than previously appreciated. In this review we discuss the role of microglia in the normal brain and their phenotypic heterogeneity and how this may play a role in AD-related pathophysiology. We touch on what is known about their ability to recognize and clear Abeta peptides as well as more controversial topics, including various activation states of microglia and the ability of peripheral macrophages or monocytes to infiltrate the brain.

PMID: 20205644 [PubMed - as supplied by publisher]

Mechanisms of Mononuclear Phagocyte Recruitment in Alzheimer's Disease.

Hickman SE, El Khoury J

Mechanisms of Mononuclear Phagocyte Recruitment in Alzheimer's Disease.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Hickman SE, El Khoury J

Alzheimer's disease (AD) is associated with a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the principal cells involved, and they accumulate at perivascular sites of beta-amyloid (Abeta) deposition and in senile plaques. Recent evidence suggests that mononuclear phagocyte accumulation in the AD brain is dependent on chemokines. CCL2, a major monocyte chemokine, is upregulated in the AD brain. Interaction of CCL2 with its receptor CCR2 regulates mononuclear phagocyte accumulation in a mouse model of AD. CCR2 deficiency leads to lower mononuclear phagocyte accumulation and is associated with higher brain Abeta levels, specifically around blood vessels, suggesting that monocytes accumulate at sites of Abeta deposition in an initial attempt to clear these deposits and stop or delay their neurotoxic effects. Indeed, enhancing mononuclear phagocyte accumulation delays progression of AD. Here we review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the potential roles of additional chemokines and their receptors in this process. We also propose a multi-step model for recruitment of mononuclear phagocytes into the brain. The first step involves egress of monocyte/microglial precursors from the bone marrow into the blood. The second step is crossing the blood-brain barrier to the perivascular areas and into the brain parenchyma. The final step includes movement of monocytes/microglia from areas of the brain that lack any amyloid deposition to senile plaques. Understanding the mechanism of recruitment of mononuclear phagocytes to the AD brain is necessary to further understand the role of these cells in the pathogenesis of AD and to identify any potential therapeutic use of these cells for the treatment of this disease.

PMID: 20205643 [PubMed - as supplied by publisher]

Re-balancing of Inflammation and Abeta Immunity as a Therapeutic for Alzheimer's Disease-View from the Bedside.

Colton M, Wilcock DM

Re-balancing of Inflammation and Abeta Immunity as a Therapeutic for Alzheimer's Disease-View from the Bedside.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Colton M, Wilcock DM

Since the original identification of microglia as a principal player in the brain's innate immune response, microglial activation has been widely studied. Recent studies suggest that microglial responses are heterogeneous, requiring a more precise definition of the functional outcomes of their participation in disease. Similarly to other tissue macrophages, microglia respond to inflammatory or injurious stimuli in the CNS in a pre-programmed manner that is designed to both kill and to set the stage for repair and resolution of the disease. In vitro studies on acute immune responses have provided key information on the initiation, signaling pathways and products of activated macrophages. However, in chronic neurodegenerative diseases such as Alzheimer's disease where in vivo analyses are critical to understanding the long-term disease processes, our knowledge of the integrated tissue immune response and the outcome of this immune activity to neurons and other glia over the extended course of disease is more limited. This is due in part to the complexity of microglial activation states and to the location of microglia in a dense neuronal network. Classical activation, alternative activation and acquired deactivation are each found in the brain during chronic neuroinflammatory diseases and may demonstrate regional differences in expression levels. This review will identify "markers" that can be used to explore inflammatory states in the brain and will discuss the likely functional outcomes when these cytoactive factors are expressed. A broad-based functional view is provided that is designed to more fully explore the balance between inflammo-toxic and inflammo-resolution factors that govern chronic disease progression.

PMID: 20205642 [PubMed - as supplied by publisher]

Re-Balancing of Inflammation and Abeta Immunity as a Therapeutic for Alzheimer's Disease-View from the Bedside.

Fiala M

Re-Balancing of Inflammation and Abeta Immunity as a Therapeutic for Alzheimer's Disease-View from the Bedside.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Fiala M

Morbidities of aging and Alzheimer's disease (AD) have been related to defective functions of both T cells and macrophages leading to brain amyloidosis and inflammation. In AD patients, "inflammaging" may be associated with an increase of incompetent memory T cells and inflammatory cytokines produced by macrophages, whereas defective clearance of amyloid-beta 1-42 (Abeta) may be related to defective transcription of immune genes necessary for Abeta phagocytosis, beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase and Toll-like receptors. However, AD shows considerable heterogeneity of disease manifestations and mechanisms. The approaches to re-balancing Abeta immunity and inflammation are being pursued in transgenic animal models and peripheral blood mononuclear cells of patients. The regulatory signaling pathways of microglial phagocytosis and inflammation involving co-receptors and transforming growth factor-beta have been considerably clarified in animal studies. Natural immunostimulating therapies using vitamin D3 and curcuminoids have been developed in macrophages of AD patients. AD patients possess two types of macrophages: a majority has "Type I", which are improved by curcuminoids and vitamin D3; whereas a minority has "Type II" responding positively to vitamin D3 but not to curcuminoids. Other nutritional substances, such as plant polyphenols and omega-3 fatty acids, may inhibit inflammation and stimulate immunity. More invasive immune approaches involve Abeta vaccine and cytokine antagonists. Increased inflammation may represent the "first hit", and defective transcription of immune genes the "second hit" in the pathogenesis of AD.

PMID: 20205641 [PubMed - as supplied by publisher]

Amyloid-beta Immunotherapy for Alzheimer's Disease.

Fu HJ, Liu B, Frost JL, Lemere CA

Amyloid-beta Immunotherapy for Alzheimer's Disease.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Fu HJ, Liu B, Frost JL, Lemere CA

Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients; however, none of them modify disease progression. Amyloid-beta (Abeta peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to Abeta as a target for treatment. Abeta immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active Abeta vaccine was halted due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine Abeta immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive Abeta immunotherapy are underway. In this review, we will provide an update of Abeta immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying Abeta immunotherapy for AD.

PMID: 20205640 [PubMed - as supplied by publisher]

Abeta DNA Vaccination for Alzheimer's Disease: Focus on Disease Prevention.

Cribbs DH

Abeta DNA Vaccination for Alzheimer's Disease: Focus on Disease Prevention.

CNS Neurol Disord Drug Targets. 2010 Mar 5;

Authors: Cribbs DH

Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy the antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, however because it can't be stopped if adverse events occur, it increases the risks associated with immunotherapy. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.

PMID: 20205639 [PubMed - as supplied by publisher]