Novel Interplay of KILN and MKL1 in Vascular Pathophysiology

PROJECT SUMMARY The major goal of this supplement project is to investigate whether deficiency of Myocardin related transcription factor A (MRTFA, MKL1), a key activator of vascular pathologies, reduces the burden of Alzheimer’s disease (AD) and AD-associated dementia. AD is a neurodegenerative condition and the most common cause of dementia. Clinical intervention through targeting Aβ remains unsuccessful, indicating that the simplistic Aβ theory is unable to account for the full mechanism behind AD. Indeed, recent studies from epidemiology, clinical imaging, and animal studies collectively point to the critical role of vascular influence on AD pathogenesis, particularly the contributory role of the impaired neurovascular unit (NVU), which results in decreased cerebral blood flow (CBF) and thus chronic cerebral hypoperfusion (CCH). Recent advances also indicates that, beyond Aβ, many unknown proteins also participate in Aβ aggregation and neuronal toxicity. As such, unveiling key regulator(s) that influence both adverse cerebral vascular remodeling and abnormal neuronal protein aggregation is of high demand for development of effective therapies for AD and AD-related dementias. In the course of working on our parent grant, we found that MKL1 expression is robustly induced by and contributes to aortic dissection and aneurysm via its potent role in activation of senescence and inflammation in VSMCs. Our new data revealed that MKL1 protein is prone to ubiquitination, a process that facilitates protein misfolding and abnormal aggregation. Consistently, a recent study showed that similar to Aβ, MKL1 is abnormally aggregated in postmortem brains of Alzheimer's disease patients. This provocative finding not only links MKL1 with AD pathology, but also suggests that MKL1 could facilitate Aβ aggregation and thus neuronal toxicity. We hypothesize that MKL1 promotes AD and AD-associated dementia via two distinct pathways: by promoting cerebral vascular pathological remodeling, leading to cerebral hypoperfusion and thus vascular dementia; and by participating in the cascade of abnormal protein aggregation to exacerbate Aβ neuronal toxicity. We will use the same mouse models that we have generated under our parent grant, and a selective small molecule MKL1 inhibitor that we have successfully applied in our recent publication to test this hypothesis through two specific aims. Aim 1 will determine the impact of MKL1 deficiency in VSMCs on cerebral vascular pathophysiology and cognitive behavior using angiotensin II model. Aim 2 will determine the impact of MKL1 systemic deficiency on the same measurements as in Aim 1 using bilateral common carotid artery stenosis (BCAS) CCH mouse model. These studies will be the logical extension to those proposed in our parent grant, the latter focuses on the interplay of MKL1 and lncRNA KILN in big arterial disease models. Successful completion of this supplement could uncover a novel druggable target for AD and AD-associated vascular dementia and provide a critical foundation for my future R01 application aiming to establish an integrative ‘neuro- vasculocentric’ paradigm for the study and possible treatment of AD.