NIH PubMed latest 20 review articles on Alzheimer's

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]

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]

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]

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]

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]

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]

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]

Novel therapeutics for Alzheimer's disease: An update.

Bonda DJ, Lee HP, Lee HG, Friedlich AL, Perry G, Zhu X, Smith MA

Novel therapeutics for Alzheimer's disease: An update.

Curr Opin Drug Discov Devel. 2010 Mar;13(2):235-46

Authors: Bonda DJ, Lee HP, Lee HG, Friedlich AL, Perry G, Zhu X, Smith MA

As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a significant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease. A considerable need exists for the development of an effective therapy to prevent, or at least delay, the progression of AD. Current hypotheses for the pathogenesis of AD are discussed in this review, with a particular emphasis on the implications of these hypotheses with respect to treatment strategies and preventive measures.

PMID: 20205057 [PubMed - in process]

Conformations and biological activities of Amyloid Beta Peptide 25-35.

Millucci L, Ghezzi L, Bernardini G, Santucci A

Conformations and biological activities of Amyloid Beta Peptide 25-35.

Curr Protein Pept Sci. 2010 Feb 1;11(1):54-67

Authors: Millucci L, Ghezzi L, Bernardini G, Santucci A

Amyloid-beta (Abeta) peptide is commonly found in human Alzheimer's disease (AD) brain and is the main component of Alzheimer amyloid plaques. The predominant forms of Abeta in the human brain are Abeta(1-40) and Abeta(1-42), but Abeta(25-35) fragment, physiologically present in elderly people, is the more toxic region and has been recently found to play a relevant role in AD, due to its peculiar aggregation properties. In this work, we review the current understanding on the conformations and biological activity of Abeta(25-35) exploring aggregation, cytotoxic and neurodegenerative properties of this fundamental Abeta fragment, in order to provide an effective starting point to better approach a pathology spread and problematic as AD.

PMID: 20201807 [PubMed - in process]

[Level of evidence for case management in Alzheimer's disease: a literature review]

Somme D, Carrier S, Trouve H, Gagnon D, Dupont O, Couturier Y, Saint-Jean O

[Level of evidence for case management in Alzheimer's disease: a literature review]

Psychol Neuropsychiatr Vieil. 2009 Dec;7 Spec No 1:29-39

Authors: Somme D, Carrier S, Trouve H, Gagnon D, Dupont O, Couturier Y, Saint-Jean O

Alzheimer's disease or related diseases patients are particularly vulnerable to fragmentation of the French system of care and support. The government has decided to implement a national plan from which two key steps are the implementation of integration and case management. We report results of a review of the literature on both the definition of these concepts and their impacts as reported in randomized controlled studies. Important differences are noticeable between studies concerning the spectrum of integration (acute and long-term care, social and health sectors, institutional and liberal sectors and financing mode notably). Case-management has multiple sense, and it must be paid attention to intensity and context of the intervention. According to available evidence, case management is likely to improve, for the person with Alzheimer's, quality of care, quality of life and quality of life of caregivers at least. Conditions for a program to be successful are adequate targeting of the target population, sufficient level of integration and adequate intensity of case management. The programs most successful and most intensive relate an effect on prevention of loss of autonomy, even death, and no extra cost. The effects on hospitalization or entry into the institution are currently hypothetical and should be further studied.

PMID: 20061231 [PubMed - in process]

Multidisciplinary perspectives for Alzheimer's and Parkinson's diseases: hydrogels for protein delivery and cell-based drug delivery as therapeutic strategies.

Multidisciplinary perspectives for Alzheimer's and Parkinson's diseases: hydrogels for protein delivery and cell-based drug delivery as therapeutic strategies.

Int J Artif Organs. 2009 Dec;32(12):836-50

Authors: Giordano C, Albani D, Gloria A, Tunesi M, Batelli S, Russo T, Forloni G, Ambrosio L, Cigada A

This review presents two intriguing multidisciplinary strategies that might make the difference in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The first proposed strategy is based on the controlled delivery of recombinant proteins known to play a key role in these neurodegenerative disorders that are released in situ by optimized polymer-based systems. The second strategy is the use of engineered cells, encapsulated and delivered in situ by suitable polymer-based systems, that act as drug reservoirs and allow the delivery of selected molecules to be used in the treatment of Alzheimer's and Parkinson's diseases. In both these scenarios, the design and development of optimized polymer-based drug delivery and cell housing systems for central nervous system applications represent a key requirement. Materials science provides suitable hydrogel-based tools to be optimized together with suitably designed recombinant proteins or drug delivering-cells that, once in situ, can provide an effective treatment for these neurodegenerative disorders. In this scenario, only interdisciplinary research that fully integrates biology, biochemistry, medicine and materials science can provide a springboard for the development of suitable therapeutic tools, not only for the treatment of Alzheimer's and Parkinson's diseases but also, prospectively, for a wide range of severe neurodegenerative disorders.

PMID: 20037888 [PubMed - indexed for MEDLINE]

ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology.

Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J

ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology.

J Neuroinflammation. 2009;6:41

Authors: Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J

The endoplasmic reticulum (ER) is involved in several crucial cellular functions, e.g. protein folding and quality control, maintenance of Ca2+ balance, and cholesterol synthesis. Many genetic and environmental insults can disturb the function of ER and induce ER stress. ER contains three branches of stress sensors, i.e. IRE1, PERK and ATF6 transducers, which recognize the misfolding of proteins in ER and activate a complex signaling network to generate the unfolded protein response (UPR). Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving misfolding and aggregation of proteins in conjunction with prolonged cellular stress, e.g. in redox regulation and Ca2+ homeostasis. Emerging evidence indicates that the UPR is activated in neurons but not in glial cells in AD brains. Neurons display pPERK, peIF2alpha and pIRE1alpha immunostaining along with abundant diffuse staining of phosphorylated tau protein. Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers. The most potent pathways are IRE1-TRAF2, PERK-eIF2alpha, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways. We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD.

PMID: 20035627 [PubMed - indexed for MEDLINE]

Imaging of sigma1 receptors in the human brain using PET and [11C]SA4503.

Toyohara J, Sakata M, Ishiwata K

Imaging of sigma1 receptors in the human brain using PET and [11C]SA4503.

Cent Nerv Syst Agents Med Chem. 2009 Sep;9(3):190-6

Authors: Toyohara J, Sakata M, Ishiwata K

Sigma(1) receptors were imaged in living human brain by positron emission tomography (PET) using [(11)C] SA4503. A dynamic 90-min scan and kinetic analysis enabled quantification of receptor density in the brain. The sigma(1) receptors were distributed throughout the brain in normal subjects, but decreased in the frontal, temporal, and occipital lobes, cerebellum and thalamus in patients with early Alzheimer's disease and in the putamen in patients with Parkinson's disease. In addition, rates of receptor occupancy by the neuroleptic haloperidol and the selective serotonin reuptake inhibitor fluvoxamine were evaluated by [(11)C]SA4503-PET and found to be high. [(11)C]SA4503-PET is useful for studying the pathophysiology of neurological and psychiatric disorders such as schizophrenia and for evaluation of the pharmacodynamics of psychiatric drugs.

PMID: 20021353 [PubMed - indexed for MEDLINE]