Cis p‐tau underlies vascular contribution to cognitive impairment and dementia, but is effectively targeted by immunotherapy

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.We first evaluated cis P-tau induction in VCID patients with no obvious AD pathology, and in mice after bilateral carotid artery stenosis (BCAS), a surgery modeling key aspects of clinical VCID. We subsequently tested if cis P-tau elimination using cis P-tau monoclonal antibody (cis mAb) reversed the VCID relevant pathology. To interrogate the upstream mechanism, we used the transgenic mice perturbing the cis P-tau counteracting isomerase Pin1 and Pin1's inhibitory kinase DAPK1, and asked if perturbation of Pin1 and DAPK1 alters cis P-tau and VCID pathology. To investigate the mechanism underlying cis P-tau pathology, we dissected the BCAS mice cortical cell-type specific transcriptome with or without the cis mAb treatment. Finally, to test if cis P-tau is sufficient to induce the pathology, we stereotaxically injected the cis P-tau purified from the injury mice brain into injury-free mice cortex and evaluate their pathological and behavioral outcome.We surprisingly find robust and early cis P-tau despite no tau tangles in VCID patients and in mice modeling key aspects of clinical VCID, likely due to the inhibition of 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. Furthermore, single-cell RNA-sequencing reveals that young VCID mice display diverse cortical cell-type specific transcriptomic changes resembling old AD patients, and the vast majority of these global changes are remarkably recovered by cis-targeted immunotherapy. Finally, purified soluble cis P-tau is sufficient to induce progressive neurodegeneration and brain dysfunction by causing axonopathy and conserved transcriptomic signature found at VCID mice and AD human patients with early pathologies.cis P-tau plays a major role in mediating VCID and its antibody may be useful for early diagnosis, prevention and treatment of cognitive impairment and dementia after neurovascular insults.