# Role of Tau Conformations in Vascular Contribution to Cognitive Impairment and Dementia

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $686,160

## Abstract

Scientific evidence continues to support vascular contributions to cognitive impairment and dementia (VCID)
such as Alzheimer's disease (AD). In fact, ~50% of dementia patients have mixed vascular and AD pathologies
in their brains. Among many potential clinical triggers, multi-embolic infarcts and cerebral hypoperfusion,
especially in the presence of aging and hypertension, are major vascular factors in VCID, referred as vascular
dementia (VaD), but underlying mechanisms remain elusive. Notably, neurofibrillary tangles composed of
hyperphosphorylated tau are a neuropathological hallmark of AD, but pure VaD human brains do not have
obvious tau tangle pathology so that little is known about the role of tau pathology in the development of VaD.
 Recently, we have identified a unique prolyl isomerase, Pin1 that prevents accumulation of the
phosphorylated Thr231-Pro motif in tau (P-tau) in the pathogenic cis conformation, but is inactivated in AD by
aging, oxidation and others. Cis P-tau is a previously unknown precursor of tau pathology that instigates and
propagates neurodegeneration and dementia associated with AD and traumatic brain injury (TBI), but can be
blocked by cis mAb. In our pilot studies, we found robust cis P-tau in neurovascular unit cells without tau tangle
pathology in pure VaD human brains and mouse models after multi-embolic infarcts or cerebral hypoperfusion.
Furthermore, purified cis P-tau was toxic both to neurons and brain microvascular endothelial cells and also
caused brain dysfunction in mice, both of which were effectively blocked by cis mAb. Moreover, cis mAb
blocked hypoxia or serum depletion from inducing cis P-tau and cell death in vascular endothelial cells and
neurons in vitro and restored white and gray matter lesions and neurologic deficits after repetitive TBI in mice.
 In this proposal, we have assembled a team with all the requisite expertise to test our novel hypothesis
that during aging, vascular insults lead to oxidative stress that inactivates Pin1, resulting in accumulation of cis
P-tau that damages the neurovascular unit, thereby serving as an early and druggable driver of VaD. We will
first assess Pin1 inhibition and cis P-tau induction in different neurovascular unit cells, and their relationships
with vascular pathology and white matter lesions in VaD human brains and after multi-embolic infarcts or
cerebral hypoperfusion in young and old mice with or without hypertension or Pin1 knockout. We will then
purify cis P-tau proteins from VaD human brains and VaD mouse brains to characterize their biochemical
property and ability to damage neurovascular unit cells in vitro and in vivo to induce white matter lesions and
neurologic deficits relevant to VaD. Finally, we will evaluate the efficacy of cis mAb in inhibiting neurovascular
unit damage in vitro and restoring white matter lesions, delayed neurodegeneration and neurologic deficits
after multi-embolic infarcts or cerebral hypoperfusion in aged hypertensiv...

## Key facts

- **NIH application ID:** 10176320
- **Project number:** 5R01AG055559-05
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Eng H. Lo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $686,160
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176320

## Citation

> US National Institutes of Health, RePORTER application 10176320, Role of Tau Conformations in Vascular Contribution to Cognitive Impairment and Dementia (5R01AG055559-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10176320. Licensed CC0.

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