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

A PreCISe therapy for vascular dementia: Vascular contributions to cognitive impairment and dementia (VCID) are conditions arising from vascular diseases or abnormalities that result in cognitive impairments. Unfortunately, the pathophysiology of VCID remains to be elucidated. Now, Qiu et al. used samples from patients with vascular dementia and mouse models to show that cis P-tau was increased in the brain and played a major role in causing cognitive impairments in mice. A cis-specific immunotherapy had therapeutic effects in the rodent models of VCID, whereas soluble cis P-tau administration caused neurodegeneration and brain dysfunction resembling VCID. The results suggest that targeting cis P-tau could reduce memory loss and neurodegeneration in VCID. 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. [ABSTRACT FROM AUTHOR]