The APP and PS1/2 mutations linked to early onset familial Alzheimer's disease increase the extracellular concentration of A/β1-42 (43)

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Abstract

If amyloid deposition is an essential early element in the pathologic process that cause AD, then each of the genetic changes known to cause AD must cause changes that foster amyloid deposition. To investigate the effect of the APP mutations known to cause familial AD (FAD), we and others previously analyzed fibroblasts from subjects carrying these mutations or transfected cells expressing the FAD-linked APP mutations. The results of these studies showed that the FAD-linked mutations oil the amino (βAPP 670N/671L) and carboxyl (βAPP 717I, F, or G) sides of Aβ do, in fact, alter βAPP processing in a way that fosters amyloid deposition either by coordinately increasing secretion of Aβ1-40 and Aβ1-42 (43) (BAPP 670N/671L) or by selectively increasing secretion of Aβ1-42 (43) (βAPP 717 mutations), a peptide that forms insoluble amyloid fibrils more tepidly than Aβ1-40 in vitro. Recent studies have established that most FAD is caused by mutations in a novel gene on chromosome 14 referred to as presenilin 1 (PS1) and that the FAD that develops in Volga-German kindreds is caused by an homologous gene on chromosome 1 referred to as presenilin 2 (PS2). To determine whether the PS1, PS2, and APP mutations linked to familial AD (FAD) increase the extracellular concentration of Aβ42 (43) in vivo, we performed a blinded comparison of plasma Aβ levels in carriers of these mutations and controls. Aβ1-42 (43) was significantly elevated in plasma from subjects with FAD-linked PS1, PS2 N141I, APPK 670N, M671L, and APPV 717I (one subject) mutations. Aβ ending at Aβ42 (43) was also significantly elevated in fibroblast media from subjects with PS1 or PS2 mutations. Importantly, plasma Aβ42 (43) was increased in all of the presymptomatic carriers that were examined and it was not increased in the vast majority of sympotomatic sporadic AD subjects examined in a comparison of 71 elderly patients with sporadic AD and 75 controls well matched for age, sex, and ethnicity. Thus elevated Aβ42 (43) is not a secondary phenomenon of the AD state. To determine whether presenilin mutations act as true dominants, we collaborated with others to analyze Aβ1-40 and Aβ1-42 (43) in transgenic mice and transfected cells expressing wild type and mutant human presenilin transgenes under the control of the platelet-derived growth factor (PDGF) promoter. This analysis showed that expression of mutant, but not wild type human PS1 selectively increases Aβ1-42 (43) even when the endogenous mouse PS1 genes are normal. Collectively, these findings indicate that a fundamental, generalized effect of the FAD-linked APP, PS1 and PS2 mutations is to increase the extracellular concentration of Aβ42 (43). The plasma data establish that these mutations increase extracellular Aβ42 (43) in vivo. The results from transgenic mice establish that the PS1 mutations increase Aβ1- 42 (43) in the brain. This increase in Aβ1-42 (43) caused by the FAD-linked mutations is likely to be directly related to the pathogenesis of AD because Aβ42 (43) is deposited early and selectively in the senile plaques that are an invariant feature of all forms of AD. Thus our results provide strong evidence that the FAD-linked mutations all cause AD by increasing the extracellular concentration of Aβ42 (43), thereby fostering Aβ deposition, and they support the hypothesis that cerebral Aβ deposition is an essential early event in the pathogenesis of all forms of AD.

Original languageEnglish (US)
Number of pages1
JournalClinical Neurology
Volume37
Issue number12
StatePublished - Jan 1 1997

Keywords

  • APP
  • Aβ1-42
  • Familial Alzheimer's disease
  • Presenilin 1/2

ASJC Scopus subject areas

  • Clinical Neurology

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