Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo (original) (raw)
Related papers
Neuron, 1997
Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familial Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, FAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Aβ1–42 peptides that are preferentially deposited in the brains of Alzheimer Disease (AD) patients. In this report, we demonstrate that transgenic animals that coexpress an FAD-linked human PS1 variant (A246E) and a chimeric mouse/human APP harboring mutations linked to Swedish FAD kindreds (APP swe) develop numerous amyloid deposits much earlier than age-matched mice expressing APP swe and wild-type Hu PS1 or APP swe alone. These results provide evidence for the view that one pathogenic mechanism by which FAD-linked mutant PS1 causes AD is to accelerate the rate of β-amyloid deposition in brain.
Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation
Translational Psychiatry, 2021
Presenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF....
EMBO molecular medicine, 2016
As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid-β peptide (Aβ) species, which are released from a C-terminal amyloid precursor protein fragment by γ-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the Aβ42 to Aβ40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD. We now show that the very little Aβ generated by PS1 L435F consists primarily of Aβ43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of Aβ43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found Aβ43-containing plaques in brains of patients with this m...
Human Mutation, 2006
The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid β precursor protein (APP) processing in causing early-onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of Aβ42 to Aβ40 (Aβ42/Aβ40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied Aβ and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible ELISA-based in vitro method and also sought correlation with brain Aβ analyzed by image densitometry and mass spectrometry. All mutations significantly increased Aβ42/Aβ40 in vitro by significantly decreasing Aβ40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. Only for half of the mutations tested, a significant increase in absolute levels of Aβ42 was observed. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with Aβ42/Aβ40 (r = -0.89; P = 0.001) and absolute levels of Aβ42 (r = -0.83; P = 0.006), but directly with Aβ40 levels (r = 0.69; P = 0.035). These changes also partly correlated with brain Aβ42 and Aβ40 levels. Together our data suggested that Aβ40 might be protective by perhaps sequestering the more toxic Aβ42 and facilitating its clearance. Also, the in vitro method we described here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting.
Journal of Neurochemistry, 2005
Gene knockout studies in mice suggest that presenilin 1 (PS1) is the major γ-secretase and that it contributes disproportionately to amyloid β (Aβ) peptide generation from β-amyloid precursor protein (APP), whereas PS2 plays a more minor role. Based on this and other observations we hypothesized that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Aβ levels in the presence of normal PS1 alleles. Only four of the eight reported FAD mutations in PS2 have altered function in vitro suggesting that the other variants represent rare polymorphisms rather than disease-causing mutations. In support of our hypothesis, the four verified PS2 FAD mutations cause substantial changes in the Aβ 42/40 ratio, comparable with PS1 mutations that cause very-early-onset FAD. Most of the PS2 mutations also cause a significant decrease in Aβ 40, APP C-terminal fragment (CTF)γ and Notch intracellular domain (NICD) production suggesting that they are partial loss of function mutations. PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM) 5 of PS1 differentially affect CTFγ and NICD production suggesting that TM5 of PS are important for γ-secretase cleavage of APP but not Notch.
Electrica, 2018
Alzheimer's disease (AD) is a neurodegenerative disease and is identified by the detection of amyloid-plaques and neurofibrillary tangles in the brain. Amyloid precursor protein gene, presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene are responsible for this disease. PSEN2 and amyloid precursor protein (APP) gene mutations are a much rarer cause of familial AD patients. This study aims to clone the PSEN2 gene and create vectors with different mutations by directed mutagenesis. As a result of the experiments, the PSEN2 cDNA was cloned between the BamHI and KpnI cutoff points of the pBluescript II sk (+) vector. PSEN1 and PSEN2 homologs have a role in cell destiny decision and AD progress. We studied some of the PSEN2 mutations (Ala252Thr and Pro334Arg) and provided expression analysis in eukaryotic cell cultures. Amyloid β-protein (Aβ), which is produced by endoproteolytic cleavage of the APP, is considered to play a role in AD. While nominal concentration of Aβ40 is 10 times of Aβ42, the last peptide is firmly linked to AD pathogenesis. Amyloid β-protein is generated by the γ-secretase cleavage of APP onset and the progression of AD, and it is the primary ingredient of the senile plaques. The Aβ42 dodecamer plays a central role in AD. In future studies, it will be determined if there is an increase in Aβ42 protein levels, and the effect on this early onset AD can be identified.
Journal of Neurochemistry, 2002
Recent reports indicate that missense mutations on presenilin (PS) 1 are likely responsible for the main early-onset familial forms of Alzheimer's disease (FAD). Consensual data obtained through distinct histopathological, cell biology, and molecular biology approaches have led to the conclusion that these PSi mutations clearly trigger an increased production of the 42amino-acid-long species of /1-amyloid peptide (A/I). Here we show that overexpression of wild-type PSi in HK293 cells increases A/I40 secretion. By contrast, FAD-linked mutants of PSi trigger increased secretion of both A/340 and A/342 but clearly favor the production of the latter species. We also demonstrate that overexpression of the wild-type PSi augments the a-secretase-derived C-terminally truncated fragment of /3-amyloid precursor protein (APPc~)recovery, whereas transfectants expressing mutated PSi secrete drastically lower amounts of APPcr when compared with cells expressing wild-type PSi . This decrease was also observed when comparing double transfectants overexpressing wild-type /3-amyloid precursor protein and either PSi or its mutated congener Ml 46V-PS1. Altogether, our data indicate that PS mutations linked to FAD not only trigger an increased ratio of A/342 over total A/I secretion but concomitantly downregulate the production of APPa. Key Words: Familial Alzheimer's disease-Presenilin 1 -a-Secretase-APPa-~3-Amyloidpeptide-/3-Amyloid precursor protein.
The Journal of Neuroscience, 1999
Mutations in presenilin (PS) genes cause early onset familial Alzheimer's disease (FAD) by increasing production of the amyloidogenic form of amyloid  peptides ending at residue 42 (A42). To identify a PS subdomain responsible for overproduction of A42, we analyzed neuro2a cell lines expressing modified forms of PS2 that harbor an N141I FAD mutation. Deletion or addition of amino acids at the C terminus and Ile448 substitution in PS2 with the N141I FAD mutation abrogated the increase in A42 secretion, and A42 overproduction was de-pendent on the stabilization and endoproteolysis of PS2. The same C-terminal modifications in PS1 produced similar effects. Hence, we suggest that the C terminus of PS plays a crucial role in the overproduction of A42 through stabilization of endoproteolytic PS derivatives and that these derivatives may be the pathologically active species of PS that cause FAD.
Journal of Biological …, 1999
Mutant presenilins (PS) contribute to the pathogenesis of familial Alzheimer's disease (FAD) by enhancing the production of A42 from -amyloid precursor protein. Presenilins are endoproteolytically processed to N-terminal and C-terminal fragments, which together form a stable 1:1 complex. We have mapped the cleavage site in the PS2 protein by direct sequencing of its Cterminal fragment isolated from mouse liver. Three different N-terminal residues were identified starting at Val-299, Thr-301, and Leu-307 that correspond closely to the previously described N termini of the C-terminal fragment of human PS1. Mutational analysis of the PS2 cleavage site indicates that the principal endoproteolytic cleavage occurs at residues Met-298/Val-299 and that the N terminus is subsequently modified by secondary proteolytic cleavages. We have generated cleavage defective PS2 constructs, which accumulate exclusively as full-length polypeptides in transfected Neuro2a cells. Functional analysis of such cleavage defective PS2 carrying the FAD mutation Asn-141 3 Ile showed that its A42 producing activity was strongly reduced compared with cleavage-competent FAD PS2. In contrast, cleavage defective PS2 was active in rescuing the egglaying defect of a sel-12 mutant in Caenorhabditis elegans. We conclude that PS2 endoproteolytic cleavage is not an absolute requirement for its activities but may rather selectively enhance or stabilize its functions.