α‐Secretase‐Derived Product of β‐Amyloid Precursor Protein Is Decreased by Presenilin 1 Mutations Linked to Familial Alzheimer's Disease

Abstract

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 42-amino-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-SecretaseAPPa-~3-Amyloidpeptide-/3-Amyloid precursor protein. J. Neurochem. 69, 2494Neurochem. 69, -2499Neurochem. 69, (1997.Several lines of genetic evidence have delineated two loci located on chromosomes 14 and 1 clearly associated with early-onset forms of familial Alzheimer's disease (FAD) (Mullan et al., 1992;Schellenberg et al., 1992;St. George-Hyslop et al., 1992;Van Broeckhoven et al., 1992; Levy-Lahad et al., 1995b). The products of these genes have been recently identified (Levy-Lahad et al., 1995a;Li et al., 1995;Rogaev et al., 1995;Sherrington et al., 1995) and named presenilin 1 and 2 (PSI and PS2), respectively. To date, >40 missense mutations (for review, see Van Broeckhoven, 1995;Haass, 1996; and one deletion (Perez-Tur et al., 1995) occurring on PSI likely responsible for most FAD have been identified, whereas only two take place on the PS2 sequence (Levy-Lahad et al., 1995b;Rogaev et al., 1995).The typical transmembrane structure of these two homologous proteins could suggest a receptor, channel, or more structural functions. We recently documented the lack of effect of PS1 and some of its FADlinked mutated analogues on Xenopus oocyte membrane currents (Dauch et al., 1997), ruling out the possible contribution or control of this protein in the regulation of ionic currents in Xenopus oocytes. Recent studies have suggested that, more likely, PSs occur as intermediates controlling the maturation and/or routing of /I-amyloid precursor protein (,8APP). First, the neuropathological characterization of the cortex of several cases with PSI mutations leads to the predominant detection of ,8-amyloid (A/I) peptide 42 (Lemer...

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“…The most intensely studied APP mutations are the "Swedish" mutation (a 2-amino acid substitution adjacent to the NH 2 terminus of A␤; Ref. 6. Possible mechanisms of action of different apolipoprotein E isoforms in promoting or preventing age-related pathological changes in the brain and periphery.…”

“…A well-documented abnormality that results from APP mutations, as well as presenilin mutations, is increased production of A␤ [particularly A␤-(1O42)] and decreased production of sAPP␣ (6,122,216). A␤ can impair synaptic function and can render neurons vulnerable to excitotoxicity and apoptosis by the following mechanism.…”

“…In addition to increasing production of A␤, APP and presenilin mutations decrease the production of sAPP␣ (6). A decrease in sAPP␣ levels may contribute to the pathogenesis of AD, because sAPP␣ normally functions in modulating synaptic plasticity (learning and memory) and in promoting survival of neurons (90,142,230).…”

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