Amyloid-β in Alzheimer's disease: Structure, toxicity, distribution, treatment, and prospects

Abstract

Amyloid-β (Aβ) is a pivotal biomarker in Alzheimer's disease (AD), attracting considerable attention from numerous researchers. There is uncertainty regarding whether clearing Aβ is beneficial or harmful to cognitive function. This question has been a central topic of research, especially given the lack of success in developing Aβ-targeted drugs for AD. However, with the Food and Drug Administration's approval of Lecanemab as the first anti-Aβ medication in July 2023, there is a significant shift in perspective on the potential of Aβ as a therapeutic target for AD. In light of this advancement, this review aims to illustrate and consolidate the molecular structural attributes and pathological ramifications of Aβ. Furthermore, it elucidates the determinants influencing its expression levels while delineating the gamut of extant Aβ-targeted pharmacotherapies that have been subjected to clinical or preclinical evaluation. Subsequently, a comprehensive analysis is presented, dissecting the research landscape of Aβ across the domains above, culminating in the presentation of informed perspectives. Concluding reflections contemplate the supplementary advantages conferred by nanoparticle constructs, conceptualized within the framework of multivalent theory, within the milieu of AD diagnosis and therapeutic intervention, supplementing conventional modalities.

Keywords: Alzheimer's disease; Aβ; anti‐Aβ drugs; multivalency; nanodrugs.

Figure 1

Formation, circulation, deposition, and toxicity of amyloid‐β (Aβ). The amyloid precursor protein is cleaved by α‐secretase and γ‐secretase or β‐secretase and γ‐secretase, and the latter will produce Aβ. Monomer, oligomer, fibril, and plaque are different forms of Aβ in the chronological aggregation period, which will be cleared out of the brain by the clearance system (like the blood–brain barrier clear system) or deposit in the brain. Geographical deposition of Aβ will cause synaptic dysfunction, mitochondrial dysfunction, inflammation, or neurodegeneration depending on the balance of the clearance system and deposition, the structural properties of Aβ, the activities of microglia and astrocytes, and the mutation of APP, Presenin‐1/2, and APOE, which are also the targets of BACE1, anti‐Aβ antibodies, and multivalent nanoparticles. Aβ, amyloid‐β; APP, amyloid precursor protein; APOE, apolipoprotein E; PSEN‐1/2, presenin‐1/2. (Created with BioRender.com). [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Development of representative clinical drugs and laboratory experiments of Aβ therapy. Aβ, amyloid‐β; PD‐1 inhibitors, programmed death‐1 inhibitors; TREM2, triggering receptor expressed on myeloid cells 2. [Color figure can be viewed at wileyonlinelibrary.com]