A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

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. Delta tau314, the C-terminally-truncated cleavage products, are soluble and present in human brain. In addition, levels of Delta tau314 proteins are elevated in the brain of the cognitively impaired individuals compared to the cognitively normal individuals, indicating a possible role for Delta tau314 proteins in cognitive deterioration. Here we show that (1) Delta tau314 proteins are present in the inferior temporal gyrus of human brains; (2) Delta tau314 proteins are generated from all six tau splicing isoforms, (3) levels of both Casp2 and Delta tau314 proteins are elevated in cognitively impaired individuals compared to cognitively normal individuals, and (4) levels of Delta tau314 proteins show a modest predictive value for dementia. These findings advance our understanding of the characteristics of Delta tau314 proteins and their relevance to cognitive dysfunction and shed light on the contribution of Casp2-mediated Delta tau314 production to cognitive deterioration.