Familial Alzheimer's Disease Gene Research Articles

Matrix disequilibrium in Alzheimer's disease and conditions that increase Alzheimer's disease risk.

Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

Reduction of lipid peroxidase levels in EFAD mouse model

AbstractBackgroundCerebral microbleeds (MBs) are more prevalent in APOE4 carriers and associated with Alzheimer Disease (AD). Loss of cerebrovascular integrity, blood‐brain barrier breakdown, and reduced Aβ clearance are also shown by APOE4 carrier mice. In AD, increased brain amyloid coupled with increased oxidative stress may synergistically contribute to MBs prevalence. EFAD mice carrying familial dominant AD genes in combination with human apoE alleles are a model for sex differences in AD, with greater amyloid accumulation and microbleeds in female E4FAD mice.Independently, Aβ and heme from microbleeds contribute to increased oxidative stress. New data suggest increased lipid peroxidation in E4 mice at baseline as measured by 4‐HNE. Peroxiredoxin 6 (Prdx6) and glutathione peroxidase 4 (GPx4) are the only known antioxidant enzymes capable of detoxifying oxidized phospholipids.MethodPrdx6 and GPx4 were studied by Western blot in cortical lysates of 6mo old EFAD mice. To evaluate Aβ contribution, we analyzed Prdx6 and GPx4 in 2mo old EFAD mice, which show 2 to 10‐fold lower Aβ compared to 6mo EFAD mice, and 6mo old EFAD non carrier siblings (no AD‐transgene).ResultPrdx6 was decreased in E4FAD mice (M: ‐30%; F: ‐50%) compared to E3FAD mice. GPx4 was decreased only n E4FAD females (M: no change; F: ‐50%). Younger mice did not show differences in either lipid peroxidases at 2mo. Interestingly, Prdx6 but not GPx4 was reduced in 6mo old female E4FAD non carrier siblings.ConclusionOur data suggest that the decreased levels of Prdx6 in 6mo old female E4 carrier mice in absence of Aβ might impair their ability to reduce oxidized lipids and predispose them to membrane alteration. Moreover, aging and increase of Aβ load together might contribute to the reduction of GPx4 levels in APOE4 carriers and the accumulation of MBs. Additional studies are required to clarify the underlying interaction sex‐apoE allele in MBs onset and its contribution to the pathogenesis of AD.

The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.

Innate immunity is associated with Alzheimer disease (AD)1, however, the influence of immune activation on Aβ production is unknown2,3. Here, we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, establishing a mechanism by which inflammation impacts Aβ generation. Inflammatory cytokines in neurons and astrocytes induce IFITM3 which binds to γ-secretase and upregulates its activity for Aβ production. IFITM3 expression is increased with aging and familial Alzheimer disease’s genes in mouse models. Furthermore, IFITM3 knock out reduces γ-secretase activity and the formation of amyloid plaques in 5XFAD mice. IFITM3 protein is upregulated in a subset of late onset AD (LOAD) patients that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in LOAD. These findings reveal an unprecedented mechanism in which γ-secretase is modulated by IFITM3 by neuroinflammation and increases risks for AD.

Progress on loss-of-function hypothesis of presenilin-1 mutations in Alzheimer diseases

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and is associated with the accumulation of amyloid-β (Aβ) peptides in patient brains. AD can be classified into the familial type and sporadic type. Presenilin-1 (PS1) is the major risk gene for familial AD (fAD) because its mutations comprised over 80%of the total mutations causing fAD. PS1 is the catalytic subunit of the enzyme γ-secretase, which is responsible for the proteolytic cleavage of amyloid precursor protein (APP) to produce Aβ. Although novel fAD-causing mutations in PS1 are being reported increasingly, the molecular mechanisms underlying how these mutations induce fAD remain elusive. Since over 90%of the fAD-causing mutations in PS1 leads to a reduction of γ-secretase activity, the PS1 loss-of-function mutation hypothesis has been emerged, which suggests that the loss of PS1 functions may be the root cause of AD. Recently, increasing number of evidence supports this hypothesis. First, PS1 loss-of-function mutations increase the production of long-length Aβ by disturbing the cleavage sites of γ-secretase APP, thereby increasing the ratio of Aβ42/Aβ40; Second, PS1 loss-of-function mutations dysregulate endoplasmic reticulum calcium homeostasis in neurons; Third, PS1 loss-of-function mutations inhibit the autophagy activity of neurons, resulting in the abnormal accumulation of cleaved products from APP; Fourth, PS1 loss-of-function mutations alter the endocytosis and transcytosis processes in neurons, leading to neuratrophy; Fifth, PS1 loss-of-function mutations activate brain immune cells (astrocytes and microglia), which mount a strong neuroinflammation response; Last, PS1 loss-of-function mutations reduce the rates of glycolysis and the production of lactic acid, disrupting the balance of neuronal energy supply. In this article we summary the research progress on the PS1 loss-of-function hypothesis and pose several topics which would guide studies of this field in future.

The zebrafish orthologue of familial Alzheimer's disease gene PRESENILIN 2 is required for normal adult melanotic skin pigmentation.

Alzheimer’s disease is the most common form of age-related dementia. At least 15 mutations in the human gene PRESENILIN 2 (PSEN2) have been found to cause familial Alzheimer’s disease (fAD). Zebrafish possess an orthologous gene, psen2, and present opportunities for investigation of PRESENILIN function related to Alzheimer’s disease. The most prevalent and best characterized fAD mutation in PSEN2 is N141I. The equivalent codon in zebrafish psen2 is N140. We used genome editing technology in zebrafish to target generation of mutations to the N140 codon. We isolated two mutations: psen2N140fs, (hereafter “N140fs”), causing truncation of the coding sequence, and psen2T141_L142delinsMISLISV, (hereafter “T141_L142delinsMISLISV”), that deletes the two codons immediately downstream of N140 and replaces them with seven codons coding for amino acid residues MISLISV. Thus, like almost every fAD mutation in the PRESENILIN genes, this latter mutation does not truncate the gene’s open reading frame. Both mutations are homozygous viable although N140fs transcripts are subject to nonsense-mediated decay and lack any possibility of coding for an active γ-secretase enzyme. N140fs homozygous larvae initially show grossly normal melanotic skin pigmentation but subsequently lose this as they grow while retaining pigmentation in the retinal pigmented epithelium. T141_L142delinsMISLISV homozygotes retain faint skin melanotic pigmentation as adults, most likely indicating that the protein encoded by this allele retains weak γ-secretase activity. Null mutations in the human PRESENILIN genes do not cause Alzheimer’s disease so these two mutations may be useful for future investigation of the differential effects of null and fAD-like PRESENILIN mutations on brain aging.

C-PLACID - Computational PLatform for Assessment of Cognition In Dementia - EPSRC

C-PLACID - Computational PLatform for Assessment of Cognition In Dementia - EPSRC

Profiling of Differential Expression of Genes in Mice Carrying Both Mutant Presenilin 1 and Amyloid Precursor Protein Transgenes with or without Knockout of B2 Adrenergic Receptor Gene.

Alzheimer's disease (AD) is a lifelong progressive neurodegenerativa disease related with accumulation of amyloid β peptide (Aβ) produced by processing of amyloid precursor protein (APP) in the brain. In spite of several-decades effort on AD, there is still no medicine used to intervene with its pathological processes. Our previous studies made in transgenic animal models harboring familial AD genes of mutant presenilin 1 and amyloid precursor protein (APP) showed that β2AR gene knock-out (β2AR-KO) is beneficial in senile AD animals. Consistently, an epidemiological study lasted for two decades showed that the sole usage of β blockers as antihypertensive medicines is associated with fewer brain lesions and less brain shrinkage seen in senile AD patients. In order to understand why senile β2AR-KO AD mice had better learning and memory, genomic effects of β2AR-KO in the double transgenic AD mice were investigated. In the analysis, major genomic significance of β2AR-KO was directed to influence protein-processing and presentation involving membrane structure and MHC class I and II protein complex, and lysosome and hydrolase activity for protein degradation, which are critical for accumulation of amyloid β peptide, the hallmark of AD.

Neuronal and Peripheral Pentraxins Modify Glutamate Release and may Interact in Blood–Brain Barrier Failure

Neuronal pentraxin 1 (NPTX1) has been implicated in Alzheimer's disease, being present in and around dystrophic neurons in plaques, affecting glutamatergic transmission postsynaptically and mediating effects of amyloidβ. Here, we confirm the presence of NPTX1 around plaques in postmortem Alzheimer's disease brain and report that acutely applied human NPTX1 increases paired-pulse ratio at mouse CA3-CA1 hippocampal synapses, indicating a decrease in glutamate release. In contrast, chronic exposure to NPTX1, NPTX2, or NPTX receptor decreases paired-pulse ratio, mimicking some of the earliest changes in mice expressing familial Alzheimer's disease genes. The peripheral pentraxin, serum amyloid P component (SAP), causes similar synaptic effects to NPTX1. The presence of SAP on amyloid plaques in Alzheimer's disease confirms that it can enter the brain. We show that SAP and neuronal pentraxins can interact and that SAP can enter the brain if the blood-brain barrier is compromised, suggesting that peripheral pentraxins could affect central synaptic transmission via this interaction, especially in the event of blood-brain barrier breakdown.

Reduced fibrillar β-amyloid in subcortical structures in a butyrylcholinesterase-knockout Alzheimer disease mouse model

The serine hydrolase, butyrylcholinesterase (BChE) is known to have a variety of enzymatic and non-enzymatic functions. In the brain, BChE is expressed mainly in glia, white matter and in distinct populations of neurons in areas important in cognition. In Alzheimer's disease (AD), many β-amyloid (Aβ) plaques become associated with BChE activity, the significance of which is unclear. A mouse model of AD containing five familial AD genes (5XFAD) also exhibits Aβ plaques associated with BChE. We developed a comparable strain (5XFAD/BChE-KO) that is unable to synthesize BChE and reported diminished fibrillar Aβ deposits in the cerebral cortex of 5XFAD/BChE-KO mice, compared to 5XFAD counterparts at the same age. This effect was most significant in male mice. The present study extends comparison of the two strains with a detailed examination of fibrillar Aβ plaque burden in other regions of the brain that typically accumulate pathology and exhibit neurodegeneration. This work demonstrates that, as in the cerebral cortex, the absence of BChE leads to diminished fibrillar Aβ deposition in amygdala, hippocampal formation, thalamus and basal ganglia. This reduction is statistically significant in males, with a trend towards such reduction in female mice.

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD +/- /human APOE+/+). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.

First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.

Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease.

White matter changes in familial Alzheimer's disease.

Familial Alzheimer's disease (FAD) resulting from gene mutations in PSEN1, PSEN2 and APP is associated with changes in the brain. The aim of this study was to investigate changes in grey matter (GM), white matter (WM) and the cerebrospinal fluid (CSF) in FAD. Ten mutation carriers (MCs) with three different mutations in PSEN1 and APP and 20 noncarriers (NCs) were included in the study. Three MCs were symptomatic and seven were presymptomatic (pre-MCs). Whole-brain GM volume as well as fractional anisotropy (FA) and mean diffusivity (MD) using voxel-based morphometry and tract-based spatial statistics analyses, respectively, were compared between MCs and NCs. FA and MD maps were obtained from diffusion tensor imaging. A significant increase in MD was found in the left inferior longitudinal fasciculus, cingulum and bilateral superior longitudinal fasciculus in pre-MCs compared with NCs. After inclusion of the three symptomatic MCs in the analysis, the regions became wider. The mean MD of these regions showed significant negative correlation with the CSF level of Aβ42, and positive correlations with P-tau181p and T-tau. No differences were observed in GM volume and FA between the groups. The results of this study suggest that FAD gene mutations affect WM diffusivity before changes in GM volume can be detected. The WM changes observed were related to changes in the CSF, with similar patterns previously observed in sporadic Alzheimer's disease.

Disregulation of Calcium Homeostasis Connected with Familial Alzheimer's Disease

Familial Alzheimer's disease (FAD) caused by mutations in presenilin-1 (PS1) gene in approximately 50% of cases and in Amyloid precursor protein (APP) gene in 13 % cases. It was found that FAD genes mutants affect calcium homeostasis in hippocampal neurons by disrupting Ca2+ storage in the lumen of endoplasmic reticulum (ER). In our study we used electrophysiological recordings with a patch-clamp technique in whole-cell mode and calcium imaging with Fura-2AM to study calcium channels activity, ER calcium load and ER calcium leak. We observed different effects of FAD mutated genes expressions on activity of store-operated and L-type voltage-gated calcium channels in mouse hippocampal neurons, mouse neuroblastoma Neuro2a and human neuroblastoma SK-N-SH cell lines. We found that effects of FAD PS1 mutants on calcium channels were driven by misbalance in activity of ER calcium sensors STIM1 and STIM2. The different effects were connected with calcium sensors STIM1 or STIM2 impaired signal transduction from ER to calcium channels in plasmatic membrane (PM) under control of ER calcium levels. The impaired signal transduction was revealed in live confocal imaging experiments. The enzyme activity of PS1 was involved in regulation of store-operated calcium entry in two ways: the activity of channels was depended on PS1 endoproteolysis level and APP cleavage.This work was supported by the program of “Molecular and Cellular Biology” RAS, research grants from the Russian Basic Research Foundation, grant ERA.Net RUS, research grants from the OPTEC LLC and the President of Russia Scholarship.

Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation

The hallmark of Alzheimer's disease (AD) pathology is an accumulation of amyloid β (Aβ) and phosphorylated tau, which are encoded by the amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT) genes, respectively. Less than 5% of all AD cases are familial in nature, i.e. caused by mutations in APP, PSEN1 or PSEN2. Almost all mutations found in them are related to an overproduction of Aβ1-42, which is prone to aggregation. While these genes are mutation free, their function, or those of related genes, could be compromised in sporadic AD as well. In this study, pyrosequencing analysis of post-mortem brains revealed aberrant CpG methylation in APP, MAPT and GSK3B genes of the AD brain. These changes were further evaluated by a newly developed in vitro-specific DNA methylation system, which in turn highlighted an enhanced expression of APP and MAPT. Cell nucleus sorting of post-mortem brains revealed that the methylation changes of APP and MAPT occurred in both neuronal and non-neuronal cells, whereas GSK3B was abnormally methylated in non-neuronal cells. Further analysis revealed an association between abnormal APP CpG methylation and apolipoprotein E ε4 allele (APOE ε4)-negative cases. The presence of a small number of highly methylated neurons among normal neurons contribute to the methylation difference in APP and MAPT CpGs, thus abnormally methylated cells could compromise the neural circuit and/or serve as 'seed cells' for abnormal protein propagation. Our results provide a link between familial AD genes and sporadic neuropathology, thus emphasizing an epigenetic pathomechanism for sporadic AD.

Biochemical and Morphological Characterization of the AβPP/PS/Tau Triple Transgenic Mouse Model and Its Relevance to Sporadic Alzheimer's Disease

Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been genetically altered with human familial AD genes driven by powerful promoters. However, a Tg model must accurately mirror the pathogenesis of the human disease, not merely the signature amyloid and/or tau pathology, as such hallmarks can arise via multiple convergent or even by pathogenic mechanisms unrelated to human sporadic AD. The 3 × Tg-AD mouse simultaneously expresses 3 rare familial mutant genes that in humans independently produce devastating amyloid-β protein precursor (AβPP), presenilin-1, and frontotemporal dementias; hence, technically speaking, these mice are not a model of sporadic AD, but are informative in assessing co-evolving amyloid and tau pathologies. While end-stage amyloid and tau pathologies in 3 × Tg-AD mice are similar to those observed in sporadic AD, the pathophysiological mechanisms leading to these lesions are quite different. Comprehensive biochemical and morphological characterizations are important to gauge the predictive value of Tg mice. Investigation of AβPP, amyloid-β (Aβ), and tau in the 3 × Tg-AD model demonstrates AD-like pathology with some key differences compared to human sporadic AD. The biochemical dissection of AβPP reveals different cleavage patterns of the C-terminus of AβPP when compared to human AD, suggesting divergent pathogenic mechanisms. Human tau is concomitantly expressed with AβPP/Aβ from an early age while abundant extracellular amyloid plaques and paired helical filaments are manifested from 18 months on. Understanding the strengths and limitations of Tg mouse AD models through rigorous biochemical, pathological, and functional analyses will facilitate the derivation of models that better approximate human sporadic AD.

A Comparative Study of Five Mouse Models of Alzheimer′s Disease: Cell Cycle Events Reveal New Insights into Neurons at Risk for Death

Ectopic cell cycle events (CCEs) in postmitotic neurons link the neurodegenerative process in human Alzheimer's disease (AD) with the brain phenotype of transgenic mouse models with known familial AD genes. Most reports on the mouse models use the appearance of brain amyloid pathology as a key outcome measure. In the current paper, we focus on the induction of neurodegeneration using CCEs as markers for impending neuronal loss. We compare 5 mouse models of familial AD for the appearance of CCEs in subcortical regions—deep cerebellar nuclei, amygdala, locus coeruleus, hippocampus, and dorsal raphe. We find that the models differ in their CCE involvement as well as in the appearance of phosphorylated tau and amyloid deposition, suggesting that each model represents a different disease phenotype. Comparison with the pattern of neuron death in human AD suggests that each may represent a distinctly different disease model when used in preclinical trials.

Correlating Familial Alzheimer's Disease Gene Mutations with Clinical Phenotype

Alzheimer's disease (AD) causes devastating cognitive impairment and an intense research effort is currently devoted to developing improved treatments for it. A minority of cases occur at a particularly young age and are caused by autosomal dominantly inherited genetic mutations. Although rare, familial AD provides unique opportunities to gain insights into the cascade of pathological events and how they relate to clinical manifestations. The phenotype of familial AD is highly variable and, although it shares many clinical features with sporadic AD, it also possesses important differences. Exploring the genetic and pathological basis of this phenotypic heterogeneity can illuminate aspects of the underlying disease mechanism, and is likely to inform our understanding and treatment of AD in the future.

Characterization of Fe, Cu and Zn in organs of PDAPP transgenic mice by XRF spectrometry

AbstractA large body of evidence indicates that abnormalities in the levels of iron, copper and zinc and their metabolism are associated with neurodegenerative diseases. However, it is difficult to decide whether any observed changes of trace elements reflect the primary disease process or are secondary to a primary process or mechanism. In the present study, Fe, Cu and Zn in organs of transgenic mice which express the familial Alzheimer's disease (AD) gene and normal mice of the same species and ages were determined by X‐ray fluorescence (XRF) spectrometry. The results show that Fe concentrations in a variety of organs and tissues were significantly increased whereas Zn concentrations decreased in the transgenic mice as compared with the ‘normals’. The levels of Cu in transgenic mice were also altered. Data obtained in the present study suggest that expression of the familial AD gene in mice results in altered homeostasis of Fe, Cu and Zn in organs of the animals, which may in turn accelerate the process of neurodegeneration. Copyright © 2006 John Wiley &amp; Sons, Ltd.

Inhibition of cyclooxygenase as potential novel therapeutic strategy in N141I presenilin-2 familial Alzheimer's disease

The present study was designed to further explore the potential cause/effect relationship between the expression of both the N141I presenilin (PS)2 mutant familial Alzheimer's disease (FAD) gene and cyclooxgenase (COX) in respect to the mechanism associated with programmed cell death in Alzheimer's disease (AD). We found that expression of mutant N141I PS2 resulting in apoptotic cell death in H4 neuronal cells coincided with >4-fold induction in the expression of the inducible form of COX-2, but not the constitutive COX-1. Moreover, we found that the expression of the N141I PS2 FAD gene strongly promoted (>2-fold) glycogen synthase kinase (GSK)-3beta activity coincidental with a reduction in the level of beta-catenin translocated from the cytoplasmic to the nuclear compartment. Most interestingly, we found that inhibition of COX-2-mediated generation of prostaglandin (PG)-E2 in H4 neuronal cells with the preferential COX-2 inhibitor nimesulide protects against N141I PS2-mediated apoptotic cell death coincidental with an inhibition of GSK-3beta activity and subsequent normalization of beta-catenin cellular distribution. The clinical relevance of this finding was confirmed by the evidence that COX-2 protein and PG-E2 concentrations were selectively increased >2-fold in the cerebral cortex of subjects harboring the N141I PS2 FAD mutation relative to wild-type PS2 AD cases. This study demonstrates for the first time that COX-2 may be a downstream effector of mutant N141I PS2-mediated apoptotic cell death and that inhibition of COX-2 may neuroprotect in AD through modulation of a GSK-3beta-beta-catenin-mediated response. The study provides support for the potential pharmacogenomic identification of N141I PS2 FAD cases that might preferentially benefit from inhibition of COX-2 during the progression of clinical dementia.