NIH PubMed latest 20 articles on Alzheimer's amyloid

An enzyme-linked immunosorbent assay to compare the affinity of chemical compounds for beta-amyloid peptide as a monomer.

Jiang C, Feng Y, Huang X, Xu Y, Zhang Y, Zhou N, Shen X, Chen K, Jiang H, Liu D

An enzyme-linked immunosorbent assay to compare the affinity of chemical compounds for beta-amyloid peptide as a monomer.

Anal Bioanal Chem. 2010 Feb 6;

Authors: Jiang C, Feng Y, Huang X, Xu Y, Zhang Y, Zhou N, Shen X, Chen K, Jiang H, Liu D

Abeta(1-42) is the proteolytic cleavage product of cleavage of the amyloid precursor protein by beta- and gamma-secretases. The aggregation of Abeta(1-42) plays a causative role in the development of Alzheimer's disease. To lock Abeta(1-42) in a homogenous state, we embedded the Abeta(1-42) sequence in an unstructured region of Bcl-x(L). Both the N-terminus and the C-terminus of Abeta(1-42) were constrained in the disordered region, whereas the conjunction did not introduce any folding to Abeta(1-42) but maintained the sequence as a monomer in solution. With Bcl-x(L)-Abeta(42), we developed an enzyme-linked immunosorbent assay to compare the affinity of compounds for monomeric Abeta(1-42). Bcl-x(L)-Abeta(42) was coated on a microplate and this was followed by incubation with different concentrations of compounds. Compounds binding to Leu17-Val24 of Abeta(1-42) inhibited the interaction between Bcl-x(L)-Abeta(42) and antibody 4G8. The method can not only reproduce the activities of the reported Abeta(1-42) inhibitors such as dopamine, tannin, and morin but can also differentiate decoy compounds that do not bind to Abeta(1-42). Remarkably, using this method, we discovered a new inhibitor that binds to monomeric Abeta(1-42) and inhibits Abeta(1-42) fibril formation. As the structure of Bcl-x(L)-Abeta(42) monomer is stable in solution, the assay could be adapted for high-throughput screening with a series of antibodies that bind the different epitopes of Abeta(1-42). In addition, the monomeric form of the Abeta(1-42) sequence in Bcl-x(L)-Abeta(42) would also facilitate the identification of Abeta(1-42) binding partners by coimmunoprecipitation, cocrystallization, surface plasmon resonance technology, or the assay as described here.

PMID: 20135308 [PubMed - as supplied by publisher]

Neuroimmunomodulation in the Pathogenesis of Alzheimer's Disease.

Morales I, Farías G, Maccioni RB

Neuroimmunomodulation in the Pathogenesis of Alzheimer's Disease.

Neuroimmunomodulation. 2010;17(3):202-204

Authors: Morales I, Farías G, Maccioni RB

Evidence has been cumulated on the role of microglia cells deregulation and alterations in their interaction patterns with brain neurons, in the pathway towards neurodegeneration in Alzheimer's disease (AD). After the failure of the amyloid hypothesis to explain AD pathogenesis, current hypotheses focus on tau self-polymerization into pathological oligomers and filaments as a major culprit for neurofibrillary degeneration. It is worth pointing out that formation of tau polymers is consistent with the clinical and neuropathological observations, and that tangles are pathognomonic of AD and related tau disorders. In this context, inflammatory processes play a major role in neuronal degeneration. On the basis of studies on microglia and neuronal cultures, together with experiments in animal models, and the clinical evidence, we postulated that a series of endogenous damage signals activate microglia cells, inducing NFkappa-beta with the consequent release of cytokine mediators such as TNF-alpha, IL-6 and IL-1beta. An overexpression of these mediators may trigger signaling cascades in neurons leading to activation of protein kinases gsk3beta, cdk5, abl kinases, along with inactivation of phosphatases such as PP1, with the resulting hyperphosphorylation and self-aggregation of tau protein into neurotoxic oligomeric species.

PMID: 20134203 [PubMed - as supplied by publisher]

Synthetic amyloid-{beta} oligomers impair long-term memory independently of cellular prion protein.

Synthetic amyloid-{beta} oligomers impair long-term memory independently of cellular prion protein.

Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300

Authors: Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G

Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-beta (Abeta) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Abeta are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Abeta-mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Abeta(1-42) oligomers impaired consolidation of the long-term recognition memory, whereas mature Abeta(1-42) fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Abeta antibody. It has been suggested that the cellular prion protein (PrP(C)) mediates the impairment of synaptic plasticity induced by Abeta. We confirmed that Abeta(1-42) oligomers interact with PrP(C), with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Abeta(1-42) oligomers are responsible for cognitive impairment in AD and that PrP(C) is not required.

PMID: 20133875 [PubMed - in process]

Mechanism of amyloid plaque formation suggests an intracellular basis of A{beta} pathogenicity.

Mechanism of amyloid plaque formation suggests an intracellular basis of A{beta} pathogenicity.

Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1942-7

Authors: Friedrich RP, Tepper K, Rönicke R, Soom M, Westermann M, Reymann K, Kaether C, Fändrich M

The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer's disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Abeta peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer's Abeta amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Abeta peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Abeta is attributed, at least in part, to intracellular aggregates.

PMID: 20133839 [PubMed - in process]

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD.

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD.

Proc Natl Acad Sci U S A. 2010 Jan 26;

Authors: Bryleva EY, Rogers MA, Chang CC, Buen F, Harris BT, Rousselet E, Seidah NG, Oddo S, Laferla FM, Spencer TA, Hickey WF, Chang TY

Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-beta, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.

PMID: 20133765 [PubMed - as supplied by publisher]

Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders.

Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders.

Neurobiol Aging. 2010 Feb 2;

Authors: Glodzik L, de Santi S, Tsui WH, Mosconi L, Zinkowski R, Pirraglia E, Wang HY, Li Y, Rich KE, Zetterberg H, Blennow K, Mehta P, de Leon MJ

Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Abeta) Abeta42/Abeta40, t-tau/Abeta42 and p-tau(231)/Abeta42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Abeta42/Abeta40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage.

PMID: 20133017 [PubMed - as supplied by publisher]

Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis.

Ha S, Furukawa R, Fechheimer M

Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis.

Neurobiol Aging. 2010 Feb 2;

Authors: Ha S, Furukawa R, Fechheimer M

Hirano bodies are cytoplasmic inclusions predominantly found in the central nervous system associated with various conditions including aging and Alzheimer's disease (AD). Since most studies of Hirano bodies have been performed in post-mortem samples, the physiological roles of Hirano bodies have not been investigated. Astrocytoma H4 cells were employed to test the hypothesis that Hirano bodies interact with and modulate signaling by the C-terminal fragment of amyloid-beta precursor protein (AICD). We demonstrated by immunofluorescence and immunoprecipitation that model Hirano bodies accumulate AICD. Since stimulation of transcription by AICD is dependent on its interaction with the nuclear adaptor protein Fe65, we examined localization of Fe65, and employed a dual luciferase reporter assay to test the effects of Hirano bodies on AICD- and Fe65-dependent modulation of gene expression. We find that both AICD and Fe65 are co-localized in model Hirano bodies. Model Hirano bodies also down-regulate both AICD-dependent apoptosis and AICD- and Fe65-dependent transcriptional activity. Thus, association of AICD and Fe65 with Hirano bodies impedes their function in promoting apoptosis and modulating transcription.

PMID: 20133016 [PubMed - as supplied by publisher]

Is there a CSF biomarker profile related to depression in elderly women?

Is there a CSF biomarker profile related to depression in elderly women?

Psychiatry Res. 2010 Feb 2;

Authors: Gudmundsson P, Skoog I, Waern M, Blennow K, Zetterberg H, Rosengren L, Gustafson D

In light of our previous observation of higher levels of cerebrospinal fluid (CSF) amyloid beta-42 (Abeta42) and CSF/serum albumin ratio in major depressive disorder (MDD), we analyzed two additional CSF biomarkers reflecting neurodegeneration-neurofilament protein light (NFL) and glial fibrillary acidic protein (GFAp)-in relationship to prevalent geriatric depression. Neuropsychiatric, physical, and lumbar puncture examinations, with DSM-III-R-based depression diagnoses and measurement of CSF levels of NFL and GFAp, were evaluated among a population-based sample of 78 elderly women (mean age, 73.9+/-3.2 years) without dementia for at least 10 years after CSF collection. Eleven (13.1%) women had MDD, and higher levels of NFL compared with women without depression. A multivariate model including age, NFL, Abeta42 and the CSF/serum albumin ratio showed that each biomarker was independently and positively associated with MDD, and that this biomarker profile explained more variation in the model compared with single or combined biomarkers. A CSF profile with higher levels of NFL, Abeta42, and CSF/serum albumin ratio may indicate neuropathological and vascular events in depression etiology. This contrasts with the well-characterized pattern of low Abeta42, higher CSF/serum albumin ratio, and higher NFL in Alzheimer's disease.

PMID: 20132991 [PubMed - as supplied by publisher]

Neuroprotective effects of emodin in rat cortical neurons against beta-amyloid-induced neurotoxicity.

Liu T, Jin H, Sun QR, Xu JH, Hu HT

Neuroprotective effects of emodin in rat cortical neurons against beta-amyloid-induced neurotoxicity.

Brain Res. 2010 Feb 1;

Authors: Liu T, Jin H, Sun QR, Xu JH, Hu HT

Accumulation of beta-amyloid protein (Abeta) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). In this study, the neuroprotective effect of emodin extracted from the traditional Chinese medicinal herb Polygonum cuspidatum Sieb. et Zucc against Abeta(25-35)-induced cell death in cultured cortical neurons was investigated. We found that pre-treatment with emodin prevented the cultured cortical neurons from beta-amyloid-induced toxicity. The preventive effect of emodin was blocked by pretreatment with a phosphatidylinositol-3-kinase (PI3K) pathway inhibitor LY294002 or an estrogen receptor (ER) specific antagonist ICI182780, but not by pretreatment with a extracellular signal-related kinases (ERK) inhibitor U0126. Furthermore, we found that emodin exposure induced the activation of the Akt serine/threonine kinase and increased the level of Bcl-2 expression. Moreover, the application of emodin for 24h was able to induce the activation of Abeta(25-35)-suppressed Akt and decrease the activation of the Jun-N-terminal kinases (JNK), but not of ERK. Interestingly, the up-regulation of Akt and Bcl-2 did not occur in the presence of LY294002 or ICI182780, suggesting that emodin-up-regulated Bcl-2 is mediated via ER and PI3K/Akt pathway. Taken together, our results suggest that emodin is an effective neuroprotective drug and is a viable candidate for treating AD.

PMID: 20132797 [PubMed - as supplied by publisher]

ANALYSIS OF beta-AMYLOID (Abeta) DEPOSITION IN THE TEMPORAL LOBE IN ALZHEIMER'S DISEASE USING FOURIER (SPECTRAL) ANALYSIS.

Armstrong RA, Cairns NJ

ANALYSIS OF beta-AMYLOID (Abeta) DEPOSITION IN THE TEMPORAL LOBE IN ALZHEIMER'S DISEASE USING FOURIER (SPECTRAL) ANALYSIS.

Neuropathol Appl Neurobiol. 2010 Jan 29;

Authors: Armstrong RA, Cairns NJ

Abstract Aim: To determine the spatial pattern of beta-amyloid (Abeta) deposition throughout the temporal lobe in Alzheimer's disease (AD). Methods: Sections of the complete temporal lobe from six cases of sporadic AD were immunolabelled with antibody against Abeta. Fourier (spectral) analysis was used to identify sinusoidal patterns in the fluctuation of Abeta deposition in a direction parallel to the pia mater or alveus. Results: Significant sinusoidal fluctuations in density were evident in 81/99 (82%) analyses. In 64% of analyses, two frequency components were present with density peaks of Abeta deposits repeating every 500-1000microm and at distances greater than 1000microm. In 25% of analyses, three or more frequency components were present. The estimated period or wavelength (number of sample units to complete one full cycle) of the first and second frequency components did not vary significantly between gyri of the temporal lobe, but there was evidence that the fluctuations of the classic deposits had longer periods than the diffuse and primitive deposits. Conclusions: (i) Abeta deposits exhibit complex sinusoidal fluctuations in density in the temporal lobe in AD, (ii) fluctuations in Abeta deposition may reflect the formation of Abeta deposits in relation to the modular and vascular structure of the cortex, and (iii) Fourier analysis may be a useful statistical method for studying the patterns of Abeta deposition both in AD and in transgenic models of disease.

PMID: 20132489 [PubMed - as supplied by publisher]

Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's Disease.

Ager RR, Fonseca MI, Chu SH, Sanderson SD, Taylor SM, Woodruff TM, Tenner AJ

Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's Disease.

J Neurochem. 2010 Feb 2;

Authors: Ager RR, Fonseca MI, Chu SH, Sanderson SD, Taylor SM, Woodruff TM, Tenner AJ

Alzheimer Disease (AD), a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta protein and neuronal loss, is the leading cause of age-related dementia in the world today. The disease is also associated with neuroinflammation, robust activation of astrocytes and microglia and evidence of activation of the complement system, localized with both fibrillar amyloid-beta (fAbeta) plaques and tangles. The observations are consistent with a complement dependent component of AD progression. We have previously shown that inhibition of the major complement receptor for C5a (CD88) with the C5a receptor antagonist (PMX205) results in a significant reduction in pathology in two mouse models of AD. To further characterize the role of complement in AD related neuroinflammation, we examined the age and disease associated expression of CD88 in brain of transgenic mouse models of AD and the influence of PMX205 on the presence of various complement activation products using flow cytometry, western blot and immunohistochemistry. CD88 was found to be upregulated in microglia, in the immediate vicinity of amyloid plaques. While thioflavine plaque load and glial recruitment is significantly reduced after treatment with PMX205, C1q remains co-localized with fAbeta plaques and C3 is still expressed by the recruited astrocytes. Thus, with PMX205, potentially beneficial activities of these early complement components may remain intact, while detrimental activities resulting from C5a-CD88 interaction are inhibited. This further supports the targeted inhibition of specific complement mediated activities as an approach for AD therapy.

PMID: 20132482 [PubMed - as supplied by publisher]

Insulin inhibits Abeta fibrillogenesis through a decrease in the GM1 ganglioside-rich microdomain of neuronal membranes.

Yamamoto N, Taniura H, Suzuki K

Insulin inhibits Abeta fibrillogenesis through a decrease in the GM1 ganglioside-rich microdomain of neuronal membranes.

J Neurochem. 2010 Jan 28;

Authors: Yamamoto N, Taniura H, Suzuki K

Abstract Type 2 diabetes is a risk factor for late-onset Alzheimer's disease. However, the underlying mechanisms remain unknown. To investigate whether insulin is associated with the assembly of amyloid beta-protein from the cell surface, we treated nerve growth factor (NGF)-treated rat pheochromocytoma 12 (PC12) cells with insulin, which is related to the development of diabetes. Insulin treatment induced a decrease in GM1 ganglioside levels in detergent-resistant membrane microdomains of NGF-treated PC12 cells. The insulin-induced effects on GM1 ganglioside levels were regulated by a phosphatidylinositol 3-kinase inhibitor, but not by an extracellular signal-regulated kinase inhibitor. Pretreatment with a protein synthesis inhibitor did not inhibit the decrease in GM1 ganglioside levels induced by insulin. In addition, insulin failed to induce formation of fibrils from soluble amyloid beta-protein or to accelerate GM1 ganglioside-induced fibril formation. Furthermore, assembly of amyloid beta-protein in cultures of NGF-treated PC12 cells was significantly decreased by insulin. These results suggest that insulin inhibits amyloid beta-protein assembly by decreasing GM1 ganglioside expression in detergent-resistant membrane microdomains of neuronal membranes.

PMID: 20132476 [PubMed - as supplied by publisher]

Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity.

Counts SE, Mufson EJ

Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity.

J Neurochem. 2010 Jan 28;

Authors: Counts SE, Mufson EJ

Abstract Degeneration of locus coeruleus (LC) noradrenergic forebrain projection neurons is an early feature of Alzheimer's disease (AD). The physiological consequences of this phenomenon are unclear, but observations correlating LC neuron loss with increased AD pathology in LC projection sites suggest that noradrenaline (NA) is neuroprotective. To investigate this hypothesis, we determined that NA protected both hNT human neuronal cultures and rat primary hippocampal neurons from amyloid-beta (Abeta(1-42) and Abeta(25-35)) toxicity. The noradrenergic co-transmitter galanin was also effective at preventing Abeta-induced cell death. NA inhibited Abeta(25-35)-mediated increases in intracellular reactive oxygen species, mitochondrial membrane depolarization, and caspase activation in hNT neurons. NA exerted its neuroprotective effects in these cells by stimulating canonical beta(1) and beta(2) adrenergic receptor signaling pathways involving the activation of cAMP response element binding protein (CREB) and the induction of endogenous nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Treatment with functional blocking antibodies for either NGF or BDNF blocked NA's protective actions against Abeta(1-42) and Abeta(25-35) toxicity in primary hippocampal and hNT neurons, respectively. Taken together, these data suggest that the neuroprotective effects of noradrenergic LC afferents result from stimulating neurotrophic NGF and BDNF autocrine or paracrine loops via beta adrenoceptor activation of the CREB pathway.

PMID: 20132474 [PubMed - as supplied by publisher]

Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease.

Ting KK, Brew BJ, Guillemin GJ

Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease.

J Neuroinflammation. 2009;6:36

Authors: Ting KK, Brew BJ, Guillemin GJ

The excitotoxin quinolinic acid (QUIN) is synthesized through the kynurenine pathway (KP) by activated monocyte lineage cells. QUIN is likely to play a role in the pathogenesis of several major neuroinflammatory diseases including Alzheimer's disease (AD). The presence of reactive astrocytes, astrogliosis, increased oxidative stress and inflammatory cytokines are important pathological hallmarks of AD. We assessed the stimulatory effects of QUIN at low physiological to high excitotoxic concentrations in comparison with the cytokines commonly associated with AD including IFN-gamma and TNF-alpha on primary human astrocytes. We found that QUIN induces IL-1beta expression, a key mediator in AD pathogenesis, in human astrocytes. We also explored the effect of QUIN on astrocyte morphology and functions. At low concentrations, QUIN treatment induced concomitantly a marked increase in glial fibrillary acid protein levels and reduction in vimentin levels compared to controls; features consistent with astrogliosis. At pathophysiological concentrations QUIN induced a switch between structural protein expressions in a dose dependent manner, increasing VIM and concomitantly decreasing GFAP expression. Glutamine synthetase (GS) activity was used as a functional metabolic test for astrocytes. We found a significant dose-dependent reduction in GS activity following QUIN treatment. All together, this study showed that QUIN is an important factor for astroglial activation, dysregulation and cell death with potential relevance to AD and other neuroinflammatory diseases.

PMID: 20003262 [PubMed - indexed for MEDLINE]

Structural and functional characterization of a novel FE65 protein product up-regulated in cognitively impaired FE65 knockout mice.

Cool BH, Zitnik G, Martin GM, Hu Q

Structural and functional characterization of a novel FE65 protein product up-regulated in cognitively impaired FE65 knockout mice.

J Neurochem. 2010 Jan;112(2):410-9

Authors: Cool BH, Zitnik G, Martin GM, Hu Q

FE65 is a multi-modular adaptor protein that binds the cytoplasmic tail of the beta-amyloid precursor protein (APP). Genetic evidence suggests that APP is intimately involved in the pathogenesis of dementias of the Alzheimer type, neurodegenerative disorders that affect multiple cognitive domains, including learning and memory. Evidence from p97FE65-specific knockout mice (lacking the 97 kDa full-length FE65 protein, p97FE65) suggests an important role for FE65 in learning and memory. Interpretation of the learning and memory phenotype, however, is complicated by the up-regulation (compared with wild-type mice) of a novel 60 kDa FE65 isoform (p60FE65). Here, we report an evidence that p60FE65 is translated from an alternative methionine, M261, on the p97FE65 transcript. Thus, p60FE65 has a shortened N-terminus, lacking part of the WW domain that is considered important for nuclear translocation and transactivation of gene expression. Consistently, p60FE65 exhibits an attenuated ability for APP-Gal4-mediated transcription as compared with p97FE65. Similar to p97FE65, however, both transfected and endogenous p60FE65 are able to translocate to the nucleus in cultured cells and in neurons. These results are consistent with earlier evidence from our laboratory that reduced FE65 nuclear signaling may contribute, in part, to the phenotypes observed in p97FE65 knockout mice.

PMID: 19860855 [PubMed - indexed for MEDLINE]