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

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

SUBMITTER: Singh B

PROVIDER: S-EPMC6778173 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Singh Balvindar B Covelo Ana A Martell-Martínez Héctor H Nanclares Carmen C Sherman Mathew A MA Okematti Emmanuel E Meints Joyce J Teravskis Peter J PJ Gallardo Christopher C Savonenko Alena V AV Benneyworth Michael A MA Lesné Sylvain E SE Liao Dezhi D Araque Alfonso A Lee Michael K MK

Acta neuropathologica 20190606 4

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less sever ...[more]

PMID: 31168644

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Project description:Co-occurrence of tau and α-synuclein pathologies in a subset of Alzheimer's disease patients has led to the idea that mixed pathologies may play a unique characteristic role in the Alzheimer's disease neurodegenerative cascade. To understand the aetiology of such mixed pathologies, we investigated cross-seeding by human recombinant tau and human recombinant α-synuclein fibrillar species in a mouse model of tauopathy (Line PS19) or synucleinopathy (Line M20). Unilateral hippocampal injection of tau fibrils or α-synuclein fibrils, and to a lesser extent tau + α-synuclein copolymer fibrils prepared from co-incubating individual recombinant monomers, induced robust phosphorylated tau pathology in PS19 mice relative to control mice. Though the tau + α-synuclein copolymer fibrils did not modulate induction of pathologies at the site of injection, examination of the whole brain showed that these copolymers exacerbated neuroanatomic transmission of seeded tau pathology compared to tau fibril-injected mice. Only α-synuclein fibrils, but not tau alone or tau + α-synuclein copolymers, triggered modest levels of endogenous phosphorylated α-synuclein pathology. Overall, data from the PS19 mice suggest that human α-synuclein fibrils can efficiently cross-seed human tau and have a modest priming effect on mouse α-synuclein, and the presence of tau fibrils does not exacerbate the priming process. In M20 mice, unilateral hippocampal injection of α-synuclein fibrils or tau fibrils induced robust bilateral phosphorylated α-synuclein pathology, while tau + α-synuclein copolymer injection resulted in restricted phosphorylated α-synuclein pathology predominantly in the ipsilateral cortex. This suggests that human tau fibrils can also induce human α-synuclein pathogenesis, and the presence of combinatorial seeds is not synergistic. None of these aggregates induced phosphorylated tau pathology in M20 mice, showing that mouse tau cannot be primed efficiently by human tau fibrils or human α-synuclein fibrils. Neuropathological analysis of the whole brain of M20 mice showed that tau + α-synuclein copolymer-injected mice had lower abundance of bilaterally transmitted α-synuclein pathologies relative to α-synuclein fibril-injected mice. Thus, the tau + α-synuclein copolymer fibrils show robust transmission properties preferentially in rodent model of tauopathies but not in synucleinopathy, probably signifying an enhanced cooperative relationship between tau and α-synuclein in the tau seeding process. Together, our data highlight the unique cross-seeding properties of tau and αSyn in neurodegenerative proteinopathies.

Dataset Information

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

Publications

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

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