The Amyloid-β Pathway in Alzheimer’s Disease

Molecular Psychiatry - Tập 26 Số 10 - Trang 5481-5503 - 2021
Harald Hampel1, John Hardy2, Kaj Blennow3, Christopher Chen4, George Perry5, Seung Hyun Kim6,7, Victor L. Villemagne8, Paul M. Thompson9, Michele Vendruscolo10, Takeshi Iwatsubo11, Colin L. Masters12, Min Cho1, Lars Lannfelt13, Jeffrey L. Cummings14, Andrea Vergallo1
1Eisai Inc., Neurology Business Group, Woodcliff Lake, NJ, USA
2UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK
3Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
4Memory Aging and Cognition Centre, Departments of Pharmacology and Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
5Department of Biology and Neurosciences Institute, University of Texas at San Antonio (UTSA), San Antonio, TX, USA
6Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea
7Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea
8Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
9USC Alzheimer's Therapeutic Research Institute, San Diego, CA, USA
10Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK
11Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
12Laureate Professor of Dementia Research, Florey Institute and The University of Melbourne, Parkville, VIC, Australia
13Uppsala University, Department of of Public Health/Geriatrics, Uppsala, Sweden
14Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, NV, USA

Tóm tắt

AbstractBreakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer’s disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.

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