Current and future implications of basic and translational research on amyloid-β peptide production and removal pathways

Abstract

Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid β-peptide (Aβ). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aβ produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aβ. We also briefly outline how the emerging knowledge about the pathways involved in Aβ generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein".

Keywords: APOE; APP; Abeta; Alzheimer; Amyloid; Dementia; EPHA1; Genetics; Neurodegeneration; Next generation sequencing; Nicastrin; PICALM; PSEN1; Presenilin; SORL1; Secretase; Tau; Vaccine.

Fig. 1

Schematic of the APP holoprotein showing the location of the transmembrane domain (orange) and the relative sites of cleavage by α-secretase, β-secretase and γ-secretase, which respectively generate: soluble sAPPα and APP-CTFα; soluble sAPPβ and APP-CTFβ; and Aβ and the amyloid intracellular domain (AICD).

Fig. 2

Schematic of APP processing pathways that are either non-amyloidogenic (α-secretase and recycling endosome pathways) or amyloidogenic (β-secretase and γ-secretase cleavage). The site of action of various AD-associated mutations is denoted in pink.

Fig. 3

3-D rendition of the 17 Å structure of the human presenilin complex under native conditions demonstrating the presence of a soluble head domain containing the ectodomain of nicastrin and a membrane-bound body containing the transmembrane domains of the other presenilin complex component proteins (PS1/PS2, PEN-2, APH1 and nicastrin). The lower panel shows the conformational shift induced by binding of a non-transition state analogue inhibitor, which results in closure of the lateral cleft and compaction of the complex. The lateral cleft may represent an important structure, which permits access of substrates to the hydrophilic catalytic pocket protected inside the centre of the body domain.

Fig. 4

Schematic diagram of the complement cascade and location of innate immune genes associated with risk for AD.