A Pathogenic Presenilin-1 Deletion Causes Abberrant Aβ42 Production in the Absence of Congophilic Amyloid Plaques (original) (raw)
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Journal of Biological Chemistry, 2002
The mutation L271V in exon 8 of the presenilin-1 (PS-1) gene was detected in an Alzheimer's disease pedigree. Neuropathological examination of affected individuals identified variant, large, non-cored plaques without neuritic dystrophy, reminiscent of cotton wool plaques. Biochemical analysis of L271V mutation showed that it increased secretion of the 42-amino acid amyloid- peptide, suggesting a pathogenic mutation. Analysis of PS-1 transcripts from the brains of two mutation carriers revealed a 17-50% increase in PS-1 transcripts with deletion of exon 8 (PS-1⌬exon8) compared with unrelated Alzheimer's disease brains. Exon trapping analysis confirmed that L271V mutation enhanced the deletion of exon 8. Western blots of brain lysates indicated that PS-1⌬exon8 was overexpressed in an affected individual. Biochemical analysis of PS-1⌬exon8 in COS and BD8 cells indicate the splice isoform is not intrinsically active but interacts with wild-type PS-1 to generate amyloid-. Western blots of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3 antibodies indicated that PS-1⌬exon8, unlike wild-type PS-1, does not interact directly with Tau or GSK-3, potential modifiers of neuritic dystrophy. We postulate that variant plaques observed in this family are due in part to the effects of PS-1⌬exon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.
Annals of Neurology, 2000
Fatal familial insomnia (FFI) is a unique hereditary prion disease with characteristic disturbances of sleep. We studied the serotonergic system in 8 FFI-affected subjects by immunohistochemistry for the serotonin-synthesizing enzyme, tryptophan hydroxylase (TH). Quantification of neurons in median raphe nuclei showed no total neuronal loss in FFI but a substantial increase of TH ؉ neurons (ϳ62%) in FFI subjects compared with controls. Our data indicate an alteration of the serotonergic system that might represent the functional substrate of some typical symptoms of FFI. Wanschitz J, Klöppel S, Jarius C, Birner P, Flicker H, Hainfellner JA, Gambetti P, Guentchev M, Budka H. Alteration of the serotonergic nervous system in fatal familial insomnia. Ann Neurol 2000;48:788 -791
Nature medicine, 1999
Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of A beta1-42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited A beta42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.
Distinguishable effects of Presenilin-1 and APP717 mutations on amyloid plaque deposition
Neurobiology of Aging, 2001
Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral A 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 A40 and A42. A 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 A42 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 A42 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 A40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of A burden in a different fashion from APP717 mutations in their familial AD brains.
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.
Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer’s Disease
Neurotoxicity Research, 2020
Alzheimer's disease (AD) is the most common cause of dementia. Mutations of presenilin (PSEN) genes that encode presenilin proteins have been found as the vital causal factors for early-onset familial AD (FAD). AD pathological features such as memory loss, synaptic dysfunction, and formation of plaques have been successfully mimicked in the transgenic mouse models that coexpress FAD-related presenilin and amyloid precursor protein (APP) variants. γ-Secretase (GS) is an enzyme that plays roles in catalyzing intramembranous APP proteolysis to release pathogenic amyloid beta (Aβ). It has been found that presenilins can play a role as the GS's catalytic subunit. FAD-related mutations in presenilins can modify the site of GS cleavage in a way that can elevate the production of longer and highly fibrillogenic Aβ. Presenilins can interact with β-catenin to generate presenilin complexes. Aforesaid interactions have also been studied to observe the mutational and physiological activities in the catenin signal transduction pathway. Along with APP, GS can catalyze intramembrane proteolysis of various substrates that play a vital role in synaptic function. PSEN mutations can cause FAD with autosomal dominant inheritance and early onset of the disease. In this article, we have reviewed the current progress in the analysis of PSENs and the correlation of PSEN mutations and AD pathogenesis.
Journal of Biological …, 1999
Presenilin-1 (PS1) facilitates ␥-secretase cleavage of the -amyloid precursor protein and the intramembraneous cleavage of Notch1. Although Alzheimer's diseaseassociated mutations in the homologous presenilin (PS2) gene elevate amyloid -peptide (A42) production like PS1 mutations, here we demonstrate that a gene ablation of PS2 (unlike that of PS1) in mice does not result in a severe phenotype resembling that of Notchablated animals. To investigate the amyloidogenic function of PS2 more directly, we mutagenized a conserved aspartate at position 366 to alanine, because the corresponding residue of PS1 is known to be required for its amyloidogenic function. Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of -amyloid precursor protein indicating a defect in ␥-secretase activity. The reduced ␥-secretase activity results in the almost complete inhibition of A and p3 production in cells stably expressing PS2 D366A, whereas cells overexpressing the wild-type PS2 cDNA produce robust levels of A and p3. Using highly sensitive in vivo assays, we demonstrate that the PS2 D366A mutation not only blocks ␥-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain. These data suggest that PS2 is functionally involved in A production and Notch signaling by facilitating similar proteolytic cleavages.
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.