Wild-type Presenilin 1 Protects against Alzheimer Disease Mutation-induced Amyloid Pathology

Abstract

Mutations in presenilin 1 (PS1) lead to dominant inheritance of early onset familial Alzheimer disease (FAD). These mutations are known to alter the ␥-secretase cleavage of the amyloid precursor protein, resulting in increased ratio of A␤42/A␤40 and accelerated amyloid plaque pathology in transgenic mouse models. To investigate the factors that drive the A␤42/A␤40 ratio and amyloid pathogenesis and to investigate the possible interactions between wildtype and FAD mutant PS1, which are co-expressed in transgenic animals, we expressed the PS1 M146V knock-in allele either on wild-type PS1 (PS1 M146V/؉ ) or PS1 null (PS1 M146V/؊ ) background and crossed these alleles with the Tg2576 APP transgenic mice. Introduction of the PS1 M146V mutation on Tg2576 background resulted in earlier onset of plaque pathology. Surprisingly, removing the wild-type PS1 in the presence of the PS1 M146V mutation (PS1 M146V/؊ ) greatly exacerbated the amyloid burden; and this was attributed to a reduction of ␥-secretase activity rather than an increase in A␤42. Our findings establish a protective role of the wild-type PS1 against the FAD mutation-induced amyloid pathology through a partial loss-of-function mechanism.The pathological hallmark defining Alzheimer disease (AD) 3 is the deposition of ␤-amyloid plaques of which the principal components are 40 -42-amino acid peptides referred to as the ␤-amyloid peptides (A␤), which are derived by proteolytic cleavages of the amyloid precursor protein (APP). APP is processed by at least three proteinases known as ␣-, ␤-, and ␥-secretases. Both ␣-and ␤-secretases (BACE1) process APP in the extracellular domain with ␣-secretase cleavage occurring inside the A␤ domain and BACE1 at the amino terminus of A␤. These proteolytic events generate APP carboxyl-terminal fragments (CTF), which serve as substrates for subsequent ␥-secretase processing, producing either p3 (product of ␣-and ␥-secretases) or A␤ peptides (product of BACE1 and ␥-secretase) (reviewed in Ref. 1). The ␥-secretase activity is executed by a high molecular weight complex of which presenilin 1 (PS1) is an essential component (reviewed in Ref. 2). As such, inhibition of PS1 leads to the accumulation of APP-CTF (3-5). The ␥-secretase exhibits relaxed sequence specificity (6). In addition to APP and in an extracellular cleavage-dependent manner, PS1 has been implicated in the processing of a growing list of type I membrane proteins including Notch (7), N-and E-cadherins (8, 9), and the tyrosinase family of proteins (Ref. 10 and reviewed in Ref. 11).Besides the ␥-sites that generate A␤40 and A␤42, PS1-dependent proteolysis also occurs at other positions including the -site (A␤46) and ⑀-site (A␤49) (12)(13)(14). Recent evidence supports a sequential cleavage model in which ⑀-cleavage at the cytosol-membrane junction serves as the initial cutting site followed by -and ␥-processing within the membrane (14). Therefore, although A␤40 and A␤42 are measurements of specific products of ␥-secretase cleavage of APP, levels of the CTF of APP as well ...

A Presenilin-1 Mutation Identified in Familial Alzheimer Disease with Cotton Wool Plaques Causes a Nearly Complete Loss of γ-Secretase Activity

“…Thus, the A␤42 deposited in cerebral CWPs in individuals with the L435F mutation is presumably the product of wild-type PS. Simple deletion of a single PS1 allele in mice does not alter the A␤42/ A␤40 ratio or promote amyloid plaque formation; on the contrary, PS1 deficiency ameliorates amyloid deposition in the brains of transgenic mice expressing mutant human APP (42)(43)(44)(45). Therefore, the intrinsic or intramolecular loss of PS1 function caused by the L435F mutation is unlikely by itself to account for the observed A␤ deposition.…”

Potent amyloidogenicity and pathogenicity of Aβ43

“…We also made another line of double-mutant mice by crossbreeding the APP Tg mice with PS1-M146V knockin mice as a positive control with which to compare the APP Tg x PS1-R278I knockin mice, given that the former mutation results in overproduction of Aβ42 rather than Aβ43 25 As expected, the PS1-M146V mutation, unlike the PS1-R278I mutation, resulted in selective accumulation of Aβ42 (Supplementary Fig. 13).…”

Pen2 and Presenilin-1 Modulate the Dynamic Equilibrium of Presenilin-1 and Presenilin-2 γ-Secretase Complexes

“…Knock-in mouse models of AD have been shown to have increased A␤42:A␤40 ratios and accelerated AD plaque deposition compared with wild type controls (31,43,44). We chose two knock-in models that harbor PS1 mutations, M146V and ⌬E10, to validate our findings that PS1 mutations can cause a shift in the equilibrium of PS1-and PS2-containing ␥-secretase complexes.…”