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Abolishing Tau cleavage by caspases at Aspartate⁴²¹ causes memory/synaptic plasticity deficits and pre-pathological Tau alterations.

ABSTRACT: TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate⁴²¹, to form a Tau metabolite known as ?Tau; ?Tau is increased in AD, due to the hyper-activation of caspases in AD brains. ?Tau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether ?Tau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called Tau^DN-that expresses a Tau mutant that cannot be cleaved by caspases. Tau^DN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that ?Tau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in ?Tau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

SUBMITTER: Biundo F

PROVIDER: S-EPMC5611732 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Abolishing Tau cleavage by caspases at Aspartate<sup>421</sup> causes memory/synaptic plasticity deficits and pre-pathological Tau alterations.

Biundo F F d'Abramo C C Tambini M D MD Zhang H H Del Prete D D Vitale F F Giliberto L L Arancio O O D'Adamio L L

Translational psychiatry 20170808 8

TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate<sup>421</sup>, to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD b ...[more]

PMID: 28786980

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Project description: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.

Dataset Information

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations.

Publications

Abolishing Tau cleavage by caspases at Aspartate<sup>421</sup> causes memory/synaptic plasticity deficits and pre-pathological Tau alterations.

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Abolishing Tau cleavage by caspases at Aspartate⁴²¹ causes memory/synaptic plasticity deficits and pre-pathological Tau alterations.