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A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington's disease patients.

ABSTRACT: Huntington's disease (HD) is a progressive neurodegenerative disease. Involuntary movements, cognitive impairment and psychiatric disturbance are the major clinical manifestations, and gradual atrophy and selective neuronal loss in the striatum and cerebral cortex are the pathologic hallmarks. HD is caused by expanded CAG trinucleotide repeats at the N-terminus of IT15 that encodes the huntingtin (HTT) protein, though the molecular mechanisms through which the mutant HTT (mHTT) exerts toxic effects remain obscure. Members of the caspase family, including caspase-2 (Casp2), play an important role in HD pathogenesis. Genetic ablation of Casp2 ameliorates cognitive and motor deficits of HD mice, though the molecular targets of Casp2 are still unclear. It is well established that the microtubule-associated protein tau potentiates cognitive dysfunction in a variety of neurodegenerative disorders, including HD. Our recent study indicates that Casp2-catalyzed tau cleavage at aspartate 314 (tau 2N4R isoform numbering system) mediates synaptotoxicity, cognitive deficits and neurodegeneration in cellular and mouse models of frontotemporal dementia; further, levels of ?tau314, the soluble, N-terminal cleavage product, are elevated in individuals with mild cognitive impairment and Alzheimer's disease, compared with cognitively normal individuals. Here, we identified the presence of ?tau314 proteins in the striatum (caudate nucleus) and prefrontal cortex (Brodmann's area 8/9) of human subjects, and showed that in both structures, levels of Casp2 and ?tau314 proteins correlate well, and both proteins are higher in HD patients than non-HD individuals. Our findings advance our understanding of the contribution of Casp2-mediated ?tau314 production to HD pathogenesis.

SUBMITTER: Liu P

PROVIDER: S-EPMC6664763 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington's disease patients.

Liu Peng P Smith Benjamin R BR Huang Eric S ES Mahesh Abhishek A Vonsattel Jean Paul G JPG Petersen Ashley J AJ Gomez-Pastor Rocio R Ashe Karen H KH

Acta neuropathologica communications 20190730 1

Huntington's disease (HD) is a progressive neurodegenerative disease. Involuntary movements, cognitive impairment and psychiatric disturbance are the major clinical manifestations, and gradual atrophy and selective neuronal loss in the striatum and cerebral cortex are the pathologic hallmarks. HD is caused by expanded CAG trinucleotide repeats at the N-terminus of IT15 that encodes the huntingtin (HTT) protein, though the molecular mechanisms through which the mutant HTT (mHTT) exerts toxic effe ...[more]

PMID: 31358058

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Project description:Mild cognitive impairment (MCI) can be an early manifestation of Alzheimer's disease (AD) pathology, other pathologic entities [e.g., cerebrovascular disease, Lewy body disease, LATE (limbic-predominant age-related TDP-43 encephalopathy)], or mixed pathologies, with concomitant AD- and non-AD pathology being particularly common, albeit difficult to identify, in living MCI patients. The National Institute on Aging and Alzheimer's Association (NIA-AA) A/T/(N) [β-Amyloid/Tau/(Neurodegeneration)] AD research framework, which classifies research participants according to three binary biomarkers [β-amyloid (A+/A-), tau (T+/T-), and neurodegeneration (N+/N-)], provides an indirect means of identifying such cases. Individuals with A+T-(N+) MCI are thought to have both AD pathologic change, given the presence of β-amyloid, and non-AD pathophysiology, given neurodegeneration without tau, because in typical AD it is tau accumulation that is most tightly linked to neuronal injury and cognitive decline. Thus, in A+T-(N+) MCI (hereafter referred to as "mismatch MCI" for the tau-neurodegeneration mismatch), non-AD pathology is hypothesized to drive neurodegeneration and symptoms, because β-amyloid, in the absence of tau, likely reflects a preclinical stage of AD. We compared a group of individuals with mismatch MCI to groups with A+T+(N+) MCI (or "prodromal AD") and A-T-(N+) MCI (or "neurodegeneration-only MCI") on cross-sectional and longitudinal cognition and neuroimaging characteristics. β-amyloid and tau status were determined by CSF assays, while neurodegeneration status was based on hippocampal volume on MRI. Overall, mismatch MCI was less "AD-like" than prodromal AD and generally, with some exceptions, more closely resembled the neurodegeneration-only group. At baseline, mismatch MCI had less episodic memory loss compared to prodromal AD. Longitudinally, mismatch MCI declined more slowly than prodromal AD across all included cognitive domains, while mismatch MCI and neurodegeneration-only MCI declined at comparable rates. Prodromal AD had smaller baseline posterior hippocampal volume than mismatch MCI, and whole brain analyses demonstrated cortical thinning that was widespread in prodromal AD but largely restricted to the medial temporal lobes (MTLs) for the mismatch and neurodegeneration-only MCI groups. Longitudinally, mismatch MCI had slower rates of volume loss than prodromal AD throughout the MTLs. Differences in cross-sectional and longitudinal cognitive and neuroimaging measures between mismatch MCI and prodromal AD may reflect disparate underlying pathologic processes, with the mismatch group potentially being driven by non-AD pathologies on a background of largely preclinical AD. These findings suggest that β-amyloid status alone in MCI may not reveal the underlying driver of symptoms with important implications for enrollment in clinical trials and prognosis.

Dataset Information

A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington's disease patients.

Publications

A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington's disease patients.

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