Amyloid β-based therapy for Alzheimer's disease: challenges, successes and future

Abstract

Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer's pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer's drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer's diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment.

Fig. 1

Amyloidogenic and non-amyloidogenic processing pathways of APP. In the amyloidogenic pathway, BACE1 first cleaves APP at the Asp¹ site to generate sAPPβ and a 99-amino acid membrane-bound C-terminal fragment (CTF) C99. Subsequently, γ-secretase cleaves C99 to release Aβ and CTFγ. Under physiological conditions (non-amyloidogenic pathways), APP is mostly cleaved first by α-secretase within Aβ domain at the Aβ Leu¹⁷ site, generating a secreted form of APP (sAPPα) and an 83-amino acid membrane-bound C-terminal fragment (CTF) C83, thus precluding Aβ production; BACE1 predominantly processes APP at the Aβ Glu¹¹ β-secretase site to generate C89, and γ-secretase cleaves C89 to produce a truncated Aβ_11-40; BACE2 cleaves APP at the Aβ Phe²⁰ θ-secretase site to generate C80 and precludes Aβ generation. APP amyloid precursor protein, BACE1 β-site APP-cleaving enzyme 1, sAPP secreted APP, CTF C-terminal fragment, Aβ amyloid-β, tAβ truncated amyloid-β, BACE2 β-site APP-cleaving enzyme 2

Fig. 2

Milestone of the amyloid cascade hypothesis and its applications. Yellow box: key research findings; blue box: the Aβ-related toxicity; green box: the diagnostic application; pink box: important drug and non-drug anti-Aβ therapies. AD Alzheimer’s disease, CSF cerebrospinal fluid, FDA food and Drug Administration, LTP long-term potentiation

Fig. 3

The generation, aggregation and pathological functions of Aβ. Aβ is generated from APP by sequential cleavage of β-secretase (beta-site APP cleaving enzyme 1, BACE1) and γ-secretase. BACE1 first cleaves APP at the Asp¹ site to generate sAPPβ and C99. Subsequently, γ-secretase cleaves C99 to release Aβ (Aβ_1-40/42 are the most common isoforms) and CTFγ. After secretion, Aβ peptides first oligomerize into different soluble species then convert their conformation into profibrils and cross-β-sheet fibrils, forming amyloid plaques. Aβ aggregates interact with tau proteins to exert the toxic effects. In addition, they contribute to other AD pathological features including neuroinflammation, oxidative stress and mitochondrial dysfunction, leading to neuronal death and dysfunction. Aβ amyloid β, APP amyloid precursor protein

Fig. 4

The physiological functions of soluble Aβ. Soluble Aβ at physiological levels has been identified to have some important functions, including induction of long-term potentiation (LTP), stimulation of neuronal differentiation, improvement of brain recover from injuries, inhibition of oxidative stress, antimicrobial activity and tumor suppression