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Neurobiol Aging. 2016 Nov;47:41-49. doi: 10.1016/j.neurobiolaging.2016.07.009. Epub 2016 Jul 25.

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

Author information

1
Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
2
Douglas Mental Health University Institute, Montreal, Quebec, Canada.
3
Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Centre National de la Recherche Scientifique (ou CNRS) ERL 8228, Centre de Recherche des Cordeliers, Paris, France.
4
Douglas Mental Health University Institute, Montreal, Quebec, Canada; Centre for Studies on Prevention of Alzheimer's Disease, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
5
Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
6
Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address: takpan.wong@mcgill.ca.

Abstract

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 α (TNFα). Treating these 1-month-old mice for 4 weeks with the TNFα 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 TNFα blockade before the onset of amyloid plaque formation prevented later synaptic deficits.

KEYWORDS:

Hippocampus; Hyperexcitability; Prevention; Prodromal; Synaptic plasticity; XPro1595

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