Abstract
Neurofibrillary tangles are a pathological hallmark of Alzheimer’s disease, and their levels correlate with the severity of cognitive dysfunction in humans. However, experimental evidence suggests that soluble tau species cause cognitive deficits and memory impairment. Our recent study suggests that caspase-2 (Casp2)-catalyzed tau cleavage at aspartate 314 mediates synaptic dysfunction and memory impairment in mouse and cellular models of neurodegenerative disorders. Δtau314, the C-terminally-truncated cleavage products, are soluble and present in human brain. In addition, levels of Δtau314 proteins are elevated in the brain of the cognitively impaired individuals compared to the cognitively normal individuals, indicating a possible role for Δtau314 proteins in cognitive deterioration. Here we show that (1) Δtau314 proteins are present in the inferior temporal gyrus of human brains; (2) Δtau314 proteins are generated from all six tau splicing isoforms, (3) levels of both Casp2 and Δtau314 proteins are elevated in cognitively impaired individuals compared to cognitively normal individuals, and (4) levels of Δtau314 proteins show a modest predictive value for dementia. These findings advance our understanding of the characteristics of Δtau314 proteins and their relevance to cognitive dysfunction and shed light on the contribution of Casp2-mediated Δtau314 production to cognitive deterioration.
Highlights
Tau is a soluble and unstructured protein, is enriched in neurons of the central nervous system (CNS), and plays an essential role in the formation and stabilization of microtubules to maintain normal neuronal structure and function[1,2]
This cohort consisted of ninety persons (twenty-four with amnestic dementia who had relatively pure Alzheimer’s disease (AD) pathology at post-mortem examination (AD dementia), thirty-three individuals who died while still being diagnosed with mild cognitive impairment (MCI) and who had at autopsy primarily AD pathology, and thirty-three individuals who were cognitively normal (CN) within 24 months before death)
We found Δtau[314] proteins derived from all six tau splicing isoforms in inferior temporal gyrus (ITG) and elevated levels of both Casp[2] and Δtau[314] proteins in the cognitively impaired (CI) individuals (AD dementia and MCI) compared to the CN individuals
Summary
Tau is a soluble and unstructured protein, is enriched in neurons of the central nervous system (CNS), and plays an essential role in the formation and stabilization of microtubules to maintain normal neuronal structure and function[1,2]. To confirm the existence of Δtau[314] proteins in human brains and their relevance to cognitive dysfunction, we analyzed post-mortem ITG specimens in a cohort from the Mayo Clinic Study of Aging at the Mayo Clinic, Rochester, MN. This cohort consisted of ninety persons (twenty-four with amnestic dementia who had relatively pure AD pathology at post-mortem examination (AD dementia), thirty-three individuals who died while still being diagnosed with mild cognitive impairment (MCI) and who had at autopsy primarily AD pathology, and thirty-three individuals who were CN within 24 months before death (twenty-eight of them remaining CN within 18 months before death)). These results contribute to our understanding of AD pathogenesis and development of biomarkers for synaptic deficits
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