Inhibiting tumor necrosis factor-α before amyloidosis prevent synaptic deficits in an Alzheimer's disease model

NEUROBIOLOGY OF AGING

卷:47

Article

Cavanagh, Chelsea^1,2  Tse, Yiu Chung¹  Huy-Binh Nguyen^1,2  Krantic, Slavica^3,4,5,6  Breitner, John C. S.^1,7,8  Quirion, Remi^1,2,8  Tak Pan Wong^1,2,8 

[1] Douglas Mental Hlth Univ Inst, 6875 LaSalle Blvd, Montreal, PQ H4H 1R3, Canada

[2] McGill Univ, Integrated Program Neurosci, Montreal, PQ, Canada

[3] UPMC Univ Paris 06, Sorbonne Univ, UMR S 1138, Ctr Rech Cordeliers, Paris, France

[4] Ctr Rech Cordeliers, INSERM, UMR S 1138, Paris, France

[5] Univ Paris 05, Sorbonne Paris Cite, UMR S 1138, Ctr Rech Cordeliers, Paris, France

[6] CNRS, ERL 8228, Ctr Rech Cordeliers, Paris, France

[7] Ctr Studies Prevent Alzheimers Dis, Montreal, PQ, Canada

[8] McGill Univ, Dept Psychiat, Montreal, PQ, Canada

关键词: Prevention;    Synaptic plasticity;    Hippocampus;    Prodromal;    XPro1595;    Hyperexcitability;   

DOI  :  10.1016/j.neurobiolaging.2016.07.009

来源: Elsevier

【 摘 要 】

Deficits in synaptic structure and function are likely to underlie cognitive impairments in Alzheimer's disease. While synaptic deficits are commonly found in animal models of amyloidosis, it is unclear how amyloid pathology may impair synaptic functions. In some amyloid mouse models of Alzheimer's disease, however, synaptic deficits are preceded by hyperexcitability of glutamate synapses. In the amyloid transgenic mouse model TgCRND8, we therefore investigated whether early enhancement of glutamatergic transmission was responsible for development of later synaptic deficits. Hippocampi from 1-month-old TgCRND8 mice revealed increased basal transmission and plasticity of glutamate synapses that was related to increased levels of tumor necrosis factor alpha (TNF alpha). Treating these 1-month-old mice for 4 weeks with the TNFa inhibitor XPro1595 prevented synaptic deficits otherwise apparent at the age of 6 months. In this mouse model at least, reversing the hyperexcitability of glutamate synapses via TNFa blockade before the onset of amyloid plaque formation prevented later synaptic deficits. (C) 2016 The Authors. Published by Elsevier Inc.

【 授权许可】

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