Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice.

Abstract

Compelling evidence supports vascular contributions to cognitive impairment and dementia (VCID) including Alzheimer's disease (AD), but the underlying pathogenic mechanisms and treatments are not fully understood. Cis P-tau is an early driver of neurodegeneration resulting from traumatic brain injury, but its role in VCID remains unclear. Here, we found robust cis P-tau despite no tau tangles in patients with VCID and in mice modeling key aspects of clinical VCID, likely because of the inhibition of its isomerase Pin1 by DAPK1. Elimination of cis P-tau in VCID mice using cis-targeted immunotherapy, brain-specific Pin1 overexpression, or DAPK1 knockout effectively rescues VCID-like neurodegeneration and cognitive impairment in executive function. Cis mAb also prevents and ameliorates progression of AD-like neurodegeneration and memory loss in mice. Furthermore, single-cell RNA sequencing revealed that young VCID mice display diverse cortical cell type-specific transcriptomic changes resembling old patients with AD, and the vast majority of these global changes were recovered by cis-targeted immunotherapy. Moreover, purified soluble cis P-tau was sufficient to induce progressive neurodegeneration and brain dysfunction by causing axonopathy and conserved transcriptomic signature found in VCID mice and patients with AD with early pathology. Thus, cis P-tau might play a major role in mediating VCID and AD, and antibody targeting it may be useful for early diagnosis, prevention, and treatment of cognitive impairment and dementia after neurovascular insults and in AD.

• Authors: Chenxi Qiu, Onder Albayram, Asami Kondo, Bin Wang, Nami Kim, Ken Arai, Cheng-Yu Tsai, Mahmoud A Bassal, Megan K Herbert, Kazuo Washida, Peter Angeli, Shingo Kozono, Joseph E Stucky, Sean Baxley, Yu-Min Lin, Yan Sun, Alexander Rotenberg, Barbara J Caldarone, Eileen H Bigio, Xiaochun Chen, Daniel G Tenen, Mark Zeidel, Eng H Lo, Xiao Zhen Zhou, Kun Ping Lu
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 596 (06 02 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 34078745 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• NIMA-Interacting Peptidylprolyl Isomerase
• tau Proteins
• PIN1 protein, human

Topics

• Alzheimer Disease (complications, therapy)
• Animals
• Brain (metabolism)
• Cognitive Dysfunction (therapy)
• Dementia, Vascular (therapy)
• Humans
• Immunotherapy
• Mice
• NIMA-Interacting Peptidylprolyl Isomerase
• tau Proteins (metabolism)