Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives
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https://doi.org/10.1007/s11427-020-1810-y
•REVIEW•
Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives 1,2,3†
Bin-lu Sun
1,2,3†
, Yang Chen
1,2,3
, Dong-yu Fan , Chi Zhu 1,2,3* Yan-jiang Wang
1,2,3
, Fan Zeng
1,2,3*
&
1
Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing 400042, China; Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing 400042, China; 3 Institute of Brain and Intelligence, Third Military Medical University, Chongqing 400042, China 2
Received June 2, 2020; accepted August 28, 2020; published online October 23, 2020
Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD) and has been regarded as the main therapeutic target for AD. However, most of the Aβ-targeted clinical trials have not succeeded. Therefore, the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated. In this review, we analyzed the challenges and critical points of the current anti-Aβ therapeutic strategies. In addition to Aβ, multiple pathological events such as tau hyperphosphorylation, oxidative stress, and neuroinflammation, which are involved in AD pathogenesis and synergistically drive disease progression, could be important targets for AD treatment. Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis. Systemic perspective addressing the disease pathogenesis within and outside the brain, as well as the multidomain intervention targeting risk factors and comorbidities, are important approaches for the therapeutic solutions of AD. Alzheimer’s disease, amyloid β, immunotherapy, β-secretase, γ-secretase, enzyme inhibitor, multi-target therapy, tertiary prevention strategy Citation:
Sun, B.L., Chen, Y., Fan, D.Y., Zhu, C., Zeng, F., and Wang, Y.J. (2020). Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives. Sci China Life Sci 63, https://doi.org/10.1007/s11427-020-1810-y
Introduction Alzheimer’s disease (AD) is the most common type of neurodegenerative diseases with the prevalence increasing exponentially with age (Reitz and Mayeux, 2014), causing a heavy social and economic burden. Extracellular senile plaques (SPs) composed of amyloid β (Aβ) and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau protein are the two neuropathological hallmarks of AD. Increasing evidence indicates the imbalance †Contributed equally to this work *Corresponding authors (Fan Zeng, email: [email protected]; Yan-Jiang Wang, email: [email protected])
between the production and clearance of Aβ as an initiating pathophysiological process of AD (Jack Jr et al., 2013; Selkoe and Hardy, 2016; Xiang et al., 2015). Accordingly, reducing the production and enhancing the clearance of Aβ are considered as crucial therapeutic strategies for AD. Currently, clearance of Aβ from the brain has been under test for AD treatment, and the Aβ-tar
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