Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF

NEUROBIOLOGY OF AGING

卷:39

Article

Jiang, Ying^1,2  Rigoglioso, Andrew¹  Peterhoff, Corrinne M.¹  Pawlik, Monika¹  Sato, Yutaka¹  Bleiwas, Cynthia¹  Stavrides, Philip¹  Smiley, John F.^1,2  Ginsberg, Stephen D.^1,2,3  Mathews, Paul M.^1,2  Levy, Efrat^1,2,4  Nixon, Ralph A.^1,2,5 

[1] Nathan S Kline Inst, Ctr Dementia Res, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA

[2] NYU Langone Med Ctr, Dept Psychiat, New York, NY USA

[3] NYU Langone Med Ctr, Dept Neurosci & Physiol, New York, NY USA

[4] NYU Langone Med Ctr, Dept Biochem & Mol Pharmacol, New York, NY USA

[5] NYU Langone Med Ctr, Dept Cell Biol, New York, NY USA

关键词: Trisomic mice;    BACE1;    APP-beta CTF;    Alzheimer's disease;    Endosomes;    Basal forebrain cholinergic neurons;   

DOI  :  10.1016/j.neurobiolaging.2015.11.013

来源: Elsevier

【 摘 要 】

beta-amyloid precursor protein (APP) and amyloid beta peptide (A beta) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-beta CTF generated by BACE1 (beta-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-beta CTF elevation but did not alter A beta 40 and A beta 42 peptide levels in brain, supporting a critical role in vivo for APP-beta CTF in the development of these abnormalities. Although ameliorative effects of BACE1 inhibition on beta-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. (C) 2016 Elsevier Inc. All rights reserved.

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