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

Peng Liu; Benjamin R. Smith; Michelle L. Montonye; Lisa J. Kemper; Kailee Leinonen-Wright; Kathryn M. Nelson; Lee Ann Higgins; Candace R. Guerrero; Todd W. Markowski; Xiaohui Zhao; Ashley J. Petersen; David S. Knopman; Ronald C. Petersen; Karen H. Ashe

doi:10.1038/s41598-020-60777-x

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

Peng Liu, Benjamin R. Smith, Michelle L. Montonye, Lisa J. Kemper, Kailee Leinonen-Wright, Kathryn M. Nelson, Lee Ann Higgins, Candace R. Guerrero, Todd W. Markowski, Xiaohui Zhao, Ashley J. Petersen, David S. Knopman, Ronald C. Petersen, Karen H. Ashe

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22 Scopus citations

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.

Original language	English (US)
Article number	3869
Journal	Scientific reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-60777-x
State	Published - Mar 2 2020

Bibliographical note

Funding 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.

Publisher Copyright:
© 2020, The Author(s).

Keywords

Alzheimer Disease/genetics
Animals
Caspase 2/genetics
Cognitive Dysfunction/genetics
Cysteine Endopeptidases/genetics
Female
Humans
Male
Mice
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41598-020-60777-x

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Liu, P., Smith, B. R., Montonye, M. L., Kemper, L. J., Leinonen-Wright, K., Nelson, K. M., Higgins, L. A., Guerrero, C. R., Markowski, T. W., Zhao, X., Petersen, A. J., Knopman, D. S., Petersen, R. C., & Ashe, K. H. (2020). A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals. Scientific reports, 10(1), Article 3869. https://doi.org/10.1038/s41598-020-60777-x

Liu, P, Smith, BR, Montonye, ML, Kemper, LJ, Leinonen-Wright, K, Nelson, KM, Higgins, LA , Guerrero, CR , Markowski, TW, Zhao, X, Petersen, AJ, Knopman, DS, Petersen, RC & Ashe, KH 2020, 'A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals', Scientific reports, vol. 10, no. 1, 3869. https://doi.org/10.1038/s41598-020-60777-x

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

abstract = "Neurofibrillary tangles are a pathological hallmark of Alzheimer{\textquoteright}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.",

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author = "Peng Liu and Smith, {Benjamin R.} and Montonye, {Michelle L.} and Kemper, {Lisa J.} and Kailee Leinonen-Wright and Nelson, {Kathryn M.} and Higgins, {Lee Ann} and Guerrero, {Candace R.} and Markowski, {Todd W.} and Xiaohui Zhao and Petersen, {Ashley J.} and Knopman, {David S.} and Petersen, {Ronald C.} and Ashe, {Karen H.}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41598-020-60777-x",

language = "English (US)",

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T1 - A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

AU - Liu, Peng

AU - Smith, Benjamin R.

AU - Montonye, Michelle L.

AU - Kemper, Lisa J.

AU - Leinonen-Wright, Kailee

AU - Nelson, Kathryn M.

AU - Higgins, Lee Ann

AU - Guerrero, Candace R.

AU - Markowski, Todd W.

AU - Zhao, Xiaohui

AU - Petersen, Ashley J.

AU - Knopman, David S.

AU - Petersen, Ronald C.

AU - Ashe, Karen H.

N1 - Funding 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. Publisher Copyright: © 2020, The Author(s).

PY - 2020/3/2

Y1 - 2020/3/2

N2 - 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.

AB - 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.

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KW - Cognitive Dysfunction/genetics

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KW - Humans

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Protein Isoforms/genetics

KW - Temporal Lobe/metabolism

KW - tau Proteins/genetics

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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