The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology

Abstract

Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

“…Down syndrome patients carry three copies of chromosome 21 in all of their cells due to chromosome missegregation during meiosis, and invariably develop AD pathology at an early age [7,21]. The data of this paper reinforce and complement the connections between trisomy 21/Down syndrome and Alzheimer's disease by providing evidence that chromosome missegregation during mitosis may also contribute to AD.…”

“…For example, many sporadic and familial AD patients, including those carrying presenilin mutations, exhibit a defect in chromosome segregation that leads to aneuploidy, including trisomy 21, in many cells throughout the body [10,26,30,31,49,50]. This finding is intriguing because individuals with full trisomy 21 (Down syndrome) all develop AD pathology at a very early age [7,21,32].…”

Baculoviruses expressing the human familial Alzheimer's disease presenilin 1 mutation lacking exon 9 increase levels of an amyloid beta-like protein in Sf9 cells

“…FAD-linked PS1 mutations result in increased generation of the highly amyloidogenic Ab42. [6][7][8] These findings indicate that PS1 is intimately involved in Ab production, a conclusion that was definitively established by the observation that PS1 deficiency eliminates g-secretase activity. 9 The identification of g-secretase inhibitors that affinity-label PS1 10,11 strongly suggests that the PS1 polypeptide forms at least part of the catalytic site of g-secretase.…”

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…Besides full-length Aß peptides, a variety of different N-truncated Ab peptides have been identified within the cored and diffuse amyloid plaques in the AD brain starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10, and pyroglutamylated Glu-11 (Antonios et al, 2013;Bayer and Wirths, 2014;Lemere et al, 1996;Saido et al, 1995).…”