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.Weshowed 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.

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

“…6B and C). Similarly, ablation of the microtubule‐associated protein tau, which has been shown to reduce epileptic activity in a variety of seizure models,28, 30, 31, 32, 33, 34 tended to reduce interictal events by roughly 50% but, if anything, tended to slightly increase the left shift in spectral power in SYN mice (Fig. 6D and E).…”

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…We therefore crossed hTau‐A152T (L1) mice and hTau‐WT (L32) mice with hAPP transgenic mice from line J20 (hAPP‐J20) (Fig 11A–D). hAPP‐J20 mice have pathologically elevated levels of human Aβ in the brain, increased risk of early death (most likely from epileptic activity), and AD‐like features, including memory problems, behavioral alterations, synaptic impairments, amyloid plaques, neuritic dystrophy, astrocytosis, and microgliosis 49, 50, 51, 52, 53.…”

“…To increase the survival of mice coexpressing hAPP/Aβ and hTau‐A152T, we crossed hTau‐A152T (L1) mice with mice from hAPP line J9 (hAPP‐J9), which express hAPP/Aβ at lower levels than hAPP‐J20 mice 50, 54, 55, 56. Among 282 offspring from crosses of hTau‐A152T (L1) and hAPP‐J9 mice, only eight were triply transgenic (Fig 11E).…”

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

“…While our work provides evidence that tau knockdown impairs learning and memory in wild‐type mice, a vast number of studies have shown that knockout of endogenous tau in AD mouse models protects against Aβ‐induced cognitive deficits (Ittner et al., 2010; Ke et al., 2012; Roberson et al., 2011; Vossel et al., 2015). For example, crossing APP mice with tau knockout mice improved spatial reference memory (Roberson et al., 2011).…”

“…For example, crossing APP mice with tau knockout mice improved spatial reference memory (Roberson et al., 2011). Mechanistically, these changes were linked to a reduced susceptibility to excitotoxicity in APP mice lacking the tau gene.…”