How Does Aging Damage the Blood Vessels in Cerebral Small Vessel Disease

We aim to impact the therapeutic intervention of dementia by identifying age-dependent vascular changes and underlying mechanisms in a model of cerebral small vessel disease.COL4A1 and COL4A2 are critical components of vascular basement membranes. Patients with COL4A1 and COL4A2 mutations develop cerebral small vessel disease (cSVD) and cognitive deficit which are faithfully represented in mutant rodent models. The first object of the proposed research is to identity age-dependent cerebrovascular changes in Col4a1 mutant mice and underlying mechanisms. Then, we will define the temporal transition of the vascular changes and test the efficacy of potential therapeutic interventions targeting identified mechanisms.

With the dramatic increase in life expectancy, the prevalence of age-related cerebrovascular disorders and dementia have become a major public health concern. Alzheimer’s disease is the most common cause of dementia and increasing evidence shows a strong association between cerebrovascular dysfunction and the development of neurological deficits and dementia. Type IV collagen (encoded by COL4A1 and COL4A2 genes) is a fundamental component of the vascular basement membrane – a sheet-like structure around blood vessels that provides physical support and acts as a platform for signaling. Patients with mutations in COL4A1 or COLA2 have very high prevalence of cerebral small vessel diseases and genetic association studies also implicate these two genes in general cerebrovascular health. Col4a1 mutant mice faithfully replicate human pathologies and show age-dependent loss of cerebrovascular tone, which could further cause cognitive impairment. Using this mouse model, this proposal aims to identify the early vascular changes and underlying molecular mechanisms that ultimately lead to the age-dependent loss of cerebrovascular tone. Additionally, we will test the efficacy of potential therapeutic strategies on age-dependent cerebrovascular pathology.

In the proposed research, we will develop novel characterizations of age-dependent cerebrovascular malfunctions in the Col4a1 mutant model of cerebral small vessel disease.

The completion of the proposed research will provide mechanistic insight into the age-dependent changes in cerebrovasculatures. Additionally, we will test the efficacy of therapeutic strategies originating from these mechanistic studies, which might impact treatment options for vascular dementia.