Distinguishable effects of presenilin-1 and APP717 mutations on amyloid plaque deposition

Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.     

Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene

Mutations in the presenilin genes (PS-1 and PS-2) cause early onset autosomal dominant Alzheimer's disease (AD). Eight early-onset, autopsy-documented familial AD kindreds were screened for mutations in PS-1, and seven different mutations were identified. Three of these were new mutations (G209V, A426P, and E120D), two were previously reported mutations in new families, and three mutations were confirmed in previously published families. Two of these new mutations are found within predicted transmembrane domains (TMDs 4, 7, and 8). The A426P mutation is the most C-terminal PS-1 mutation identified to date. Hum Mutat 11:216–221, 1998. © 1998 Wiley-Liss, Inc.     

A novel presenilin 1 mutation (Ser169del) in a Chinese family with early-onset Alzheimer's disease

Early-onset familial Alzheimer's disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Here we report a novel PSEN1 mutation in a Chinese family with autosomal dominant Alzheimer's disease with an onset age in the early 40s. Molecular genetic analysis showed a 507-509delATC mutation at codon 169, leading to the deletion of serine in residue 169 (Ser169del). The amnestic presentation and absence of other features contrast with the other two mutations at codon 169 which have been associated with myoclonic jerks and seizures.     

Familial Alzheimer's disease: genetic influences on the disease process (Review).

Alzheimer's disease (AD) has both genetic and environmental etiologies. Genetic causes include presenilin (PS) mutations on chromosomes 1 and 14, and amyloid precursor protein (APP) mutations on chromosome 21. At least two susceptibility genes also exist. In this review phenotypic differences in AD groups are described and possible differences in the mechanism(s) by which AD mutations lead to dementia are reviewed. Clinical, pathological and biochemical phenotypes distinguish AD cases with different etiologies. For example, age-at-onset and age-at-death between PS-1, PS-2, APP and sporadic AD groups differ. Also, some forms of AD are associated with more Abeta deposition others, and some AD groups have morphologically distinct Abeta deposits or other unique histopathologic features. APP-related AD mutations always occur within the Abeta portion of the APP gene, adjacent to sites where alpha-, beta- and gamma-secretase breakdown pathways operate in the expressed protein. These mutations alter APP metabolism leading to increased Abeta production. It is unknown if other AD groups are subject to identical changes in APP metabolism. Activation of apoptosis pathways, more general defects in protein transport or metabolism, differential regulation of tau kinases or other factors may also be important. Overall, data support the notion that differences occur in the disease process in etiologically distinct AD groups.     

Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease

Three mouse models of Alzheimer's disease (AD) were used to assess changes in gene expression potentially critical to amyloid beta-peptide (Abeta)-induced neuronal dysfunction. One mouse model harbored homozygous familial AD (FAD) knock-in mutations in both, amyloid precursor protein (APP) and presenilin 1 (PS-1) genes (APP(NLh/NLh)/PS-1(P264L/P264L)), the other two models harbored APP over-expression of FAD mutations (Tg2576) with the PS-1 knock-in mutation at either one or two alleles. These mouse models of AD had varying levels of Abeta40 and Abeta42 and different latencies and rates of Abeta deposition in brain. To assess changes in gene expression associated with Abeta accumulation, the Affymetrix murine genome array U74A was used to survey gene expression in the cortex of these three models both prior to and following Abeta deposition. Altered genes were identified by comparing the AD models with age-matched control littermates. Thirty-four gene changes were identified in common among the three models in mice with Abeta deposition. Among the up-regulated genes, three major classes were identified that encoded for proteins involved in immune responses, carbohydrate metabolism, and proteolysis. Down-regulated genes of note included pituitary adenylate cyclase-activating peptide (PACAP), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor I receptor (IGF-IR). In young mice without detectable Abeta deposition, there were no regulated genes common among the three models, although 40 genes were similarly altered between the two Tg2576 models with the PS-1 FAD knock-in. Finally, changes in gene expression among the three mouse models of AD were compared with those reported in human AD samples. Sixty-nine up-regulated and 147 down-regulated genes were found in common with human AD brain. These comparisons across different genetic mouse models of AD and human AD brain provide greater support for the involvement of identified gene expression changes in the neuronal dysfunction and cognitive deficits accompanying amyloid deposition in mammalian brain.     

Alzheimer's presenilin 1 is a putative membrane receptor for rab GDP dissociation inhibitor

Mutations in the presenilin 1 ( PS-1 ) gene cause Alzheimer's disease (AD). These mutations alter the processing of the amyloid precursor protein (APP) by increasing the production of the fibrillogenic amyloid fragment, Abeta1-42/43. Since the secretase activities that process APP are localized in different intracellular compartments, it is likely that membrane transport is a key factor in the pathogenesis of AD. In this report we provide evidence for a direct connection between PS-1 and membrane transport. We show that the N-terminus of PS-1 binds to rab GDP dissociation inhibitor (rabGDI), a regulatory factor in vesicle transport. In PS-1-deficient neurons we found a 2-fold decrease in the amount of rabGDI associated with membranes. Our findings are compatible with PS-1 being a membrane receptor for rabGDI. This is in line with a role of PS-1 in the regulation of protein trafficking in the ER/Golgi, which can modulate the production of Abeta.     

Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease.

Families bearing mutations in the presenilin 1 (PS1) gene develop early onset familial Alzheimer's disease (FAD). Further, some PS1 mutants enhance secretion of the longer form of amyloid beta protein (Abeta42). We constructed cDNAs encoding human PS1 harboring 28 FAD-linked mutations, and examined the effects of the expressed PS1 mutants on Abeta42 secretion in beta amyloid precursor producing COS-1 cells. All the mutants significantly enhanced the ratio of Abeta42 to total Abeta compared with wild-type PS1. However, the increase in Abeta42 ratio in cells with each PS1 mutation did not correlate with the reported age of onset of FAD caused by that mutation. These results suggest that increased Abeta42 secretion is important for the development of Alzheimer's disease (AD), but may not be the only factor contributing to the onset of AD.     

Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees

Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (P=0.0001 and 0.0006) with plasma Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at approximately 80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (P=0.04 for 4783 and P=0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.     

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.      

Antibodies to presenilin proteins detect neurofibrillary tangles in Alzheimer's disease.

Mutations in the presenilin (PS)-1 and PS-2 genes have been shown to be linked with the development of Alzheimer's disease (AD). We examined Alzheimer's brain tissue by immunohistochemistry using a set of antibodies raised to sequences shared between PS-1 and PS-2 proteins. These antibodies reacted exclusively with a subset of neurofibrillary tangles and not with neuropil threads or dystrophic neurites. Detection of the presenilin epitope in neurofibrillary tangles was observed in sporadic Alzheimer's disease brain samples and in samples from individuals carrying PS-1 and PS-2 mutations with no qualitative difference. These data indicate that both wild-type and mutant PS proteins are involved in a common pathogenic pathway in AD.     

Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms

Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. Dementia is associated with massive accumulation of fibrillary aggregates in various cortical and subcortical regions of the brain. These aggregates appear intracellularly as neurofibrillary tangles, extracellularly as amyloid plaques and perivascular amyloid in cerebral blood vessels. The causative factors in AD etiology implicate both, genetic and environmental factors. The large majority of early-onset familial Alzheimer's disease (FAD) cases are linked to mutations in the genes coding for presenilin 1 (PS1) and presenilin 2 (PS2). The corresponding proteins are 467 (PS1) and 448 (PS2) amino-acids long, respectively. Both are membrane proteins with multiple transmembrane regions. Presenilins show a high degree of conservation between species and a presenilin homologue with definite conservation of the hydrophobic structure has been identified even in the plant Arabidopsis thaliana. More than 50 missense mutations in PS1 and two missense mutations in PS2 were identified which are causative for FAD. PS mutations lead to the same functional consequence as mutations on amyloid precursor protein (APP), altering the processing of APP towards the release of the more amyloidogenic form 1-42 of Abeta (Abeta42). In this regard, the physical interaction between APP and presenilins in the endoplasmic reticulum has been demonstrated and might play a key role in Abeta42 production. It was hypothesized that PS1 might directly cleave APP. However, extracellular amyloidogenesis and Abeta production might not be the sole factor involved in AD pathology and several lines of evidence support a role of apoptosis in the massive neuronal loss observed. Presenilins were shown to modify the apoptotic response in several cellular systems including primary neuronal cultures. Some evidence is accumulating which points towards the beta-catenin signaling pathways to be causally involved in presenilin mediated cell death. Increased degradation of beta-catenin has been shown in brain of AD patients with PS1 mutations and reduced beta-catenin signaling increased neuronal vulnerability to apoptosis in cell culture models. The study of presenilin physiological functions and the pathological mechanisms underlying their role in pathogenesis clearly advanced our understanding of cellular mechanisms underlying the neuronal cell death and will contribute to the identification of novel drug targets for the treatment of AD.     

Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia

Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid beta precursor protein (APP) genes lead to early-onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset < or = 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early-onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early-onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late-onset, were negative for PSEN and APP mutations.     

ApoE genotype is a risk factor in nonpresenilin early-onset alzheimer's disease families

The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset of Alzheimer's disease (AD). We analyzed the effect of the ApoE genotype in two distinct early-onset familial AD groups: families with a mutation in the presenilin-1 gene (PS-1) on chromosome 14, and families without a mutation detectable in the PS-1, presenilin-2 (PS-2), and the amyloid precursor protein (APP) gene (non-PS early-onset familial AD). The ApoE genotype is clearly shown not to modulate age of onset in families with a mutation in the PS-1 gene and families with no lesion detectable in either the presenilin or APP gene. The effects of a double dose of ApoE4 on age of onset were not assessed in the PS-1 AD families due to the lack of any affected ApoE4 homozygotes in the sample set; this insufficiency will need to be assessed in further studies. There was no association between the ApoE4 allele and AD in the PS-1 families. Non-PS early-onset AD families were shown to have a significantly higher frequency of ApoE4 compared to controls and the PS-1 AD group. These observations are important and suggest that 1) other genetic and environmental factors modify the AD phenotype in PS-1 and non-PS early-onset families; and 2) the ApoE4 allele is a significant risk factor in the etiology of non-PS early-onset AD and will be a useful adjunct in the diagnosis of unaffected family members. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:117–121, 1998. © 1998 Wiley-Liss, Inc.     

Systematic genetic study of Alzheimer disease in Latin America: Mutation frequencies of the amyloid β precursor protein and presenilin genes in Colombia*

Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid β precursor protein (APP) genes lead to early‐onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset ≤ 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early‐onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early‐onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late‐onset, were negative for PSEN and APP mutations. © 2001 Wiley‐Liss, Inc.     

A transgenic rat model of Alzheimer's disease with extracellular Abeta deposition

Many transgenic mouse models of Alzheimer's disease (AD) that deposit amyloid (Abeta) have been produced, but development of an Abeta-depositing rat model has not been successful. Here, we describe a rat model with extracellular fibrillar Abeta deposition. Two lines of Sprague Dawley rats with transgenes expressing human amyloid precursor protein (APP) with the familial AD (FAD) mutations K670N/M671L and K670N/M671L/V717I were crossed. Abeta production in the double homozygous rats was sufficient for deposition by 17-18 months of age. The age of onset of Abeta deposition was reduced by crossing in a third rat line carrying a human presenilin-1 (PS-1) transgene with the FAD M146V mutation. The triple homozygous line had an onset of Abeta deposition by 7 months of age. Deposits appeared similar to those observed in the mouse models and displayed surrounding glial and phosphorylated tau reactivity. Abeta levels measured by ELISA were comparable to those reported in mouse models, suggesting that substantially greater amounts of soluble Abeta are not required in the rat to generate Abeta deposition.     

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Mutations in the presenilin 1 gene cause most early onset familial Alzheimer's disease (FAD). Here, we report that a defect in the cell cycle - improper chromosome segregation - can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: (1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knocking mice are aneuploid by metaphase chromosome analysis and in situ hybridization. (2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 h, including trisomy 21. (3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer's disease are discussed.     

Association between presenilin-1 polymorphism and maternal meiosis II errors in Down syndrome

Several lines of evidence suggest a shared genetic susceptibility to Down syndrome (DS) and Alzheimer disease (AD). Rare forms of autosomal-dominant AD are caused by mutations in the APP and presenilin genes (PS-1 and PS-2). The presenilin proteins have been localized to the nuclear membrane, kinetochores, and centrosomes, suggesting a function in chromosome segregation. A genetic association between a polymorphism in intron 8 of the PS-1 gene and AD has been described in some series, and an increased risk of AD has been reported in mothers of DS probands. We therefore studied 168 probands with free trisomy 21 of known parental and meiotic origin and their parents from a population-based material, by analyzing the intron 8 polymorphism in the PS-1 gene. An increased frequency of allele 1 in mothers with a meiosis II error (70.8%) was found compared with mothers with a meiosis I error (52.7%, P < 0.01), with an excess of the 11 genotype in the meiosis II mothers. The frequency of allele 1 in mothers carrying apolipoprotein E (APOE) epsilon4 allele (68.0%) was higher than in mothers without epsilon4 (52.2%, P < 0.01). We hypothesize that the PS-1 intronic polymorphism might be involved in chromosomal nondisjunction through an influence on the expression level of PS-1 or due to linkage disequilibrium with biologically relevant polymorphisms in or outside the PS-1 gene.     

Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life

Over 160 rare genetic variants in presenilin 1 (PSEN1) are known to cause Alzheimer's disease (AD). In this study we screened a family with early-onset AD for mutations in PSEN1 using direct DNA sequencing. We identified a novel PSEN1 genetic variant which results in the substitution of a Proline with an Alanine at codon 117 (P117A). The P117A variant was present in all demented individuals and fifty percent of at risk individuals. This variant occurs at a site where three other disease-causing variants have been previously observed. In vitro functional studies demonstrate that the P117A variant results in an altered Abeta42/total Abeta ratio consistent with an AD causing mutation. The P117A variant is a novel mutation in PSEN1, which causes early-onset AD in an autosomal dominant manner.     

Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer''s disease

Many different mutations, causative of Alzheimer's disease, have been found in the presenilin-1 gene (PS-1). We have developed a screening method based on denaturing gradient gel electrophoresis (DGGE), which allows the mutational analysis of the whole exon 9 of PS-1. Upon the screening of a Spanish sample of early onset familial Alzheimer disease cases, we have found a novel mutation in the PS-1 gene. The mutation (a T to G transition) results in a change of the amino acid at position 282 of the presenilin protein from leucine to arginine. This mutation is located in the hydrophobic domain number 7 (exon 9) close to the site of physiological cleavage processing. The average of onset of the affected members of this family is 43±5 years, and the average age of exitus of affected members is 56±3 years. The possibility to determine the specific pathologic mechanisms of this mutation is now open.     

Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online

Familial Alzheimer's disease (AD) is an autosomal dominant disorder characterized by memory impairment and multiple cognitive deficits which occurs in mid to late life. Early onset AD has been associated with mutations in three genes, of which presenilin 1 (PS1) mutations are the most frequent. We sequenced the open reading frame from genomic DNA of a series of 21 early onset AD (AD3) UK families in which there were at least two affected individuals in two or more generations with a diagnosis of probable or definite AD. We found PS1 mutations in six of these families with no sequence variation in the remaining 15. The six families contained between them five different mutations of which two, I143F and P436S, have not been found elsewhere. I143F shows incomplete penetration within the affected family. P436S is the most carboxy-terminal presenilin 1 mutation reported to date.