title: Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer's disease model.
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.
authors.affiliation: Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Cavanagh
authors.affiliation: Douglas Mental Health University Institute, Montreal, Quebec, Canada.
authors.forename: Yiu Chung
authors.initials: YC
authors.lastname: Tse
authors.affiliation: Douglas Mental Health University Institute, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
authors.forename: Huy-Binh
authors.initials: HB
authors.lastname: Nguyen
authors.affiliation: 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.
authors.forename: Slavica
authors.initials: S
authors.lastname: Krantic
authors.affiliation: 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.
authors.forename: John C S
authors.initials: JC
authors.lastname: Breitner
authors.affiliation: 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.
authors.forename: Remi
authors.initials: R
authors.lastname: Quirion
authors.affiliation: 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.
authors.forename: Tak Pan
authors.initials: TP
authors.lastname: Wong
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009473:Neuronal Plasticity; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D013569:Synapses / Q000473:pathology* / Q000502:physiology*; D009435:Synaptic Transmission; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595; D018698:Glutamic Acid
keywords: Hippocampus; Hyperexcitability; Prevention; Prodromal; Synaptic plasticity; XPro1595