title: Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.
abstract: Alzheimer's disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn. We showed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded whole-cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA. eroberson@uab.edu
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
authors.forename: Brian
authors.initials: B
authors.lastname: Halabisky
authors.forename: Jong W
authors.initials: JW
authors.lastname: Yoo
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yao
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chin
authors.forename: Fengrong
authors.initials: F
authors.lastname: Yan
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wu
authors.forename: Patricia
authors.initials: P
authors.lastname: Hamto
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Palop
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000401:mortality; D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D004569:Electroencephalography; D005260:Female; D006624:Hippocampus / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009415:Nerve Net / Q000502:physiology*; D009473:Neuronal Plasticity; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D012640:Seizures / Q000378:metabolism / Q000503:physiopathology; D013045:Species Specificity; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn