Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of α-synucleinopathy

Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highlyrelated α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Geneticand neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, itis currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD andDLB is less severe than in Alzheimer’s disease. Previously, we found that familial Parkinson’s disease-linked human mutantA53T αS causes aberrant localization of the microtubule-associated protein tau to postsynaptic spines in neurons, leadingto postsynaptic deficits. Thus, we directly tested if the synaptic and memory deficits in a mouse model of α-synucleinopathy(TgA53T) are mediated by tau. TgA53T mice exhibit progressive memory deficits associated with postsynaptic deficits inthe absence of obvious neuropathological and neurodegenerative changes in the hippocampus. Significantly, removal ofendogenous mouse tau expression in TgA53T mice (TgA53T/mTau−/−), achieved by mating TgA53T mice to mouse tauknockoutmice, completely ameliorates cognitive dysfunction and concurrent synaptic deficits without affecting αS expressionor accumulation of selected toxic αS oligomers. Among the known tau-dependent effects, memory deficits in TgA53Tmice were associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling wasabsent in TgA53T/mTau−/− mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficitsare mechanistically linked. Our results directly implicate tau as a mediator of specific human mutant A53T αS-mediatedabnormalities related to deficits in hippocampal neurotransmission and suggest a mechanism for memory impairment thatoccurs as a consequence of synaptic dysfunction rather than synaptic or neuronal loss. We hypothesize that these initial synapticdeficits contribute to network hyperexcitability which, in turn, exacerbate cognitive dysfunction. Our results indicatethat these synaptic changes present potential therapeutic targets for amelioration of memory deficits in α-synucleinopathies.