Jiang Ying, Rigoglioso Andrew, Peterhoff Corrinne M, Pawlik Monika, Sato Yutaka, Bleiwas Cynthia, Stavrides Philip, Smiley John F, Ginsberg Stephen D, Mathews Paul M, Levy Efrat, Nixon Ralph A
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA.
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA.
Neurobiol Aging. 2016 Mar;39:90-8. doi: 10.1016/j.neurobiolaging.2015.11.013. Epub 2015 Dec 2.
β-amyloid precursor protein (APP) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-βCTF generated by BACE1 (β-APP cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial BACE1 genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome. Partially reducing BACE1 by deleting one BACE1 allele blocked development of age-related endosome enlargement in the medial septal nucleus, cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive medial septal nucleus neurons. BACE1 reduction normalized APP-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for APP-βCTF in the development of these abnormalities. Although ameliorative effects of BACE1 inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of BACE1 modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in Down syndrome and AD.
β-淀粉样前体蛋白（APP）和β-淀粉样肽（Aβ）与阿尔茨海默病（AD）的发病机制密切相关，尽管最近有证据表明，由β-分泌酶1（BACE1）产生的APP-βCTF与早期AD中内吞异常和胆碱能神经变性的发展有关。我们发现，部分降低BACE1基因可预防唐氏综合征Ts2小鼠模型中这些与AD相关的病理特征。通过删除一个BACE1等位基因来部分降低BACE1，可阻止内侧隔核、大脑皮层和海马体中与年龄相关的内体增大的发展，以及胆碱乙酰转移酶（ChAT）阳性内侧隔核神经元的丢失。BACE1的减少使APP-βCTF升高恢复正常，但并未改变脑中Aβ40和Aβ42肽的水平，这支持了APP-βCTF在这些异常发展中的关键作用。尽管先前在AD小鼠模型中已注意到抑制BACE1对β-淀粉样变性和突触蛋白水平的改善作用，但我们的结果强调了调节BACE1在唐氏综合征和AD中内吞功能障碍和胆碱能神经变性的治疗靶点方面的额外潜在价值。
