Potent amyloidogenicity and pathogenicity of Aβ43

Saito, Takashi; Suemoto, Takahiro; Brouwers, Nathalie; Sleegers, Kristel; Funamoto, Satoru; Mihira, Naomi; Matsuba, Yukio; Yamada, Kazuyuki; Nilsson, Per; Takano, Jiro; Nakagawa, Masaki; Iwata, Nobuhisa; Broeckhoven, Christine Van; Ihara, Yasuo; Saido, Takaomi C.

doi:10.1038/nn.2858

Cited by 274 publications

(322 citation statements)

References 49 publications

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“…For example, Aβ43 was reported to exhibit more potent amyloidogenicity and pathogenicity (34). Existing data suggest that absolute levels of Aβ42 are not as important as the altered ratios of the Aβ peptides, most notably the ratio of Aβ42/Aβ40 (22,33,35).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Dang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of γ-secretase), making modulation of γ-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact γ-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to γ-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Aβ42, Aβ40, and Aβ38. The molar ratio of the cleavage products Aβ42 over Aβ40 by PSH is nearly identical to that by γ-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of γ-secretase also modulate PSH similarly in terms of the Aβ42/Aβ40 ratio. Structural analysis reveals association of a known γ-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of γ-secretase.A myloid precursor protein (APP) is initially cleaved by β-secretase in the extracellular space, producing a membrane-tethered, 99-residue carboxyl-terminal fragment known as APP C99 (1). APP C99 then undergoes sequential cleavages by γ-secretase, first at the e sites, yielding Aβ49/Aβ48, and eventually at the γ-sites, generating Aβ42/Aβ40/Aβ38 (2-4) (Fig. 1A). The 230-kDa γ-secretase contains four components: presenilin (PS), Pen-2, Aph-1, and nicastrin (NCT), of which PS1 is the target of most mutations derived from early-onset familial Alzheimer's disease (FAD) patients. Rather than abolishing the protease activity of γ-secretase, these mutations are thought to increase the molar ratio of Aβ42 over Aβ40 (2).Among the cleavage products of γ-secretase, Aβ42 is particularly prone to aggregation, leading to formation of β-amyloid plaque in the brain and presumably causing Alzheimer's disease (3). Other FAD-derived mutations map to APP and PS2, lending support to the causal relationship between formation of β-amyloid plaque and Alzheimer's disease (5). Therapeutic intervention of Alzheimer's disease may directly benefit from in vitro investigation of γ-secretase and discovery of its potential modulators (6). Unfortunately, such effort has been hampered by the difficulty in expression, purification, and manipulation of the complex protease. This problem persists despite recent breakthroughs in structural elucidation of γ-secretase and nicastrin (7,8).The intramembrane aspartate protease PSH from the archaeon Methanoculleus marisnigri JR1 shares 19% sequence identity and 53% sequence similarity with human PS1 (hPS1). The signature motifs for catalysis, ΦYDΦΦ (Φ for a hydrophobic residue) on transmembrane segment 6 (TM6) and ΦGΦGD on TM7, are identical between PSH and hPS1. PSH can be readily overexpressed in Escheri...

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Section: Discussionmentioning

confidence: 99%

Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Dang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Mice overexpressing this peptide showed a selective hippocampal neurodegeneration [31], and passive immunization against this peptide reduces the amyloid burden in an APP/PS1 double-transgenic mouse model [30]. In addition, Aβ1-43, generated by a disease-related PS1 mutant, was recently profiled as an overlooked neurotoxic isoform as this species was shown to have a higher propensity to aggregate and was more toxic than Aβ1-42 [32].…”

Section: Challenges In Targeting Amyloidmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…Faster aggregation leads to earlier A␤ deposition, which is believed to promote its toxicity (5)(6)(7). Recently, A␤ was discovered as a novel toxic peptide in AD (8,9). In addition to A␤ peptides starting with aspartate as the first amino acid (A␤ 1 ), several N-terminal truncated and modified A␤ species have also been described.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%