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.
Bibliographical noteFunding Information:
This study, including experimental design, data collection, analysis and interpretation, and manuscript preparation, is supported by Minnesota Partnership #16.01 to K.H.A. and R.C.P. and National Institutes of Health U01-AG06786 and P50-AG016574 to R.C.P. The authors thank Ms. Kris Johnson, R.N. for coordinating brain tissue preparation and transportation and managing demographic, neuropathological, and clinical information of individuals involved in this study. The authors thank Ms. Elizabeth L. Steuer for proofreading and helpful revision advice.
© 2020, The Author(s).
- Alzheimer Disease/genetics
- Caspase 2/genetics
- Cognitive Dysfunction/genetics
- Cysteine Endopeptidases/genetics
- Mice, Transgenic
- Protein Isoforms/genetics
- Temporal Lobe/metabolism
- tau Proteins/genetics
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural