A closer look at pathogenic amyloid-β in Alzheimer’s disease using cryo-electron microscopy: a narrative review

Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder that affects millions of people worldwide. The identification of amyloid-β in Alzheimer’s disease brains, together with the association of mutations in the amyloid-β precursor protein with Alzheimer’s disease pathology, is the basis of the amyloid cascade hypothesis, which suggests that amyloid-β plays a central role in Alzheimer’s disease pathogenesis. Recent studies have further highlighted the role of intraneuronal amyloid-β in Alzheimer’s disease development. Moreover, the success of anti-amyloid-β immunotherapies supports the amyloid cascade hypothesis, emphasizing the importance of targeting specific amyloid-β conformations to achieve better therapeutic outcomes. In recent years, cryo-electron microscopy has become an invaluable tool for obtaining near-atomic resolution images of protein assemblies, and multiple structures of brain-derived amyloid fibrils have been elucidated. In this article, we review the role of pathogenic amyloid-β according to the amyloid cascade hypothesis and explore the relationship between intraneuronal amyloid-β accumulation and the development of key pathological features of Alzheimer’s disease—amyloid plaques and neurofibrillary tangles. We also connect cryo-electron microscopy structures of amyloid-β aggregates with amyloid-β-targeting treatment and highlight recent advances and future research directions. The application of cryo-electron microscopy can provide molecular insights into amyloid-β structure, which is expected to help uncover the underlying mechanisms of Alzheimer’s disease and provide new therapeutic strategies for the clearance of amyloid-β aggregates.