Associations of CSF BACE1 with amyloid pathology, neurodegeneration, and cognition in Alzheimer’s disease

IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2024-06-10 DOI:10.1007/s00401-024-02750-w

Feng Gao, Mengguo Zhang, Qiong Wang, Ming Ni, Chang Liu, Kexue Deng, Qiang Xie, Shicung Wang, Jiong Shi, Yong Shen, For CANDI Consortium

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引用次数: 0

Abstract

Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-β (Aβ) in Alzheimer’s disease (AD) patients. However, the side effects observed in clinical trials of BACE1 inhibitors, including reduction in brain volume and cognitive worsening, suggest that the exact role of BACE1 in AD pathology is not fully understood. To further investigate this, we examined cerebrospinal fluid (CSF) levels of BACE1 and its cleaved product sAPPβ that reflects BACE1 activity in the China Aging and Neurodegenerative Disorder Initiative cohort. We found significant correlations between CSF BACE1 or sAPPβ levels and CSF Aβ40, Aβ42, and Aβ42/Aβ40 ratio, but not with amyloid deposition detected by 18F-Florbetapir PET. Additionally, CSF BACE1 and sAPPβ levels were positively associated with cortical thickness in multiple brain regions, and higher levels of sAPPβ were linked to increased cortical glucose metabolism in frontal and supramarginal areas. Interestingly, individuals with higher baseline levels of CSF BACE1 exhibited slower rates of brain volume reduction and cognitive worsening over time. This suggests that increased levels and activity of BACE1 may not be the determining factor for amyloid deposition, but instead, may be associated with increased neuronal activity and potentially providing protection against neurodegeneration in AD.

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CSF BACE1 与阿尔茨海默病的淀粉样病理、神经变性和认知能力的关系。

Β位点淀粉样前体蛋白（APP）裂解酶（BACE1）是阿尔茨海默病（AD）患者体内产生淀粉样-β（Aβ）的关键蛋白酶。然而，在 BACE1 抑制剂的临床试验中观察到的副作用（包括脑容量减少和认知能力恶化）表明，BACE1 在阿尔茨海默病病理学中的确切作用尚未完全明了。为了进一步研究这个问题，我们在中国老龄化与神经退行性疾病研究项目队列中检测了脑脊液（CSF）中 BACE1 及其裂解产物 sAPPβ（反映 BACE1 活性）的水平。我们发现 CSF BACE1 或 sAPPβ 水平与 CSF Aβ40、Aβ42 和 Aβ42/Aβ40 比值之间存在明显相关性，但与 18F-Florbetapir PET 检测到的淀粉样沉积无关。此外，CSF BACE1和sAPPβ水平与多个脑区的皮质厚度呈正相关，较高的sAPPβ水平与额叶和边际上区皮质葡萄糖代谢增加有关。有趣的是，CSF BACE1 基线水平较高的个体随着时间的推移，脑容量减少和认知能力恶化的速度较慢。这表明，BACE1水平和活性的增加可能并不是淀粉样蛋白沉积的决定性因素，相反，它可能与神经元活性的增加有关，并可能为防止AD的神经变性提供保护。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.