Abstract
Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid β-protein (Aβ) levels or aggregation. Here, we identified a novel APP mutation, located within the Aβ sequence (AβD7H), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aβ production, Aβ42/40 ratio and prolonged Aβ42 oligomer state with higher neurotoxicity. Because the D7H mutant Aβ has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aβ to ion. When co-incubated with Zn2+ or Cu2+, AβD7H aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a “double punch” effect on elevating both Aβ production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aβ N-terminal region potentially modulates APP processing and Aβ aggregation, and further provides a genetic indication of the importance of Zn2+ and Cu2+ in the etiology of AD.
Highlights
Alzheimer’s disease (AD) is characterized neuropathologically by progressive brain deposition of the amyloid b peptide (Ab), which is generated by proteolytic cleavage of amyloid precursor protein (APP) by b- and c-secretases (Fig. 1A)
APP overexpressing cell culture study indicated that the D7H mutation enhances the amyloidogenic cleavage pathway and raises Ab production and the Ab42/40 ratio
In vitro examination indicated that the D7H mutation shifts Ab variants have 40 (Ab40) aggregation into the fibril-prone pathway and Ab42 aggregation into the oligomerprone pathway
Summary
Alzheimer’s disease (AD) is characterized neuropathologically by progressive brain deposition of the amyloid b peptide (Ab), which is generated by proteolytic cleavage of amyloid precursor protein (APP) by b- and c-secretases (Fig. 1A). The abnormal aggregation and accumulation of neurotoxic Ab have been proposed as the primary driving force for AD in the amyloid hypothesis [1]. Ab aggregation undergoes multiple pathways with a variety of intermediates/oligomers formation. The current notion is that low molecular weight (LMW) assemblies such as soluble oligomers and protofibrils, but not fibril, are the primary toxic structures of Ab [2,3]. Due to the highly dynamic nature of Ab assemblies and the technical limitation, biochemical features of toxic Ab aggregates remain unclear [4]
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