Cerebral small vessel diseases (CSVD) are a major cause of vascular cognitive impairment and dementia (VCID) in the elderly, account for a significant number of ischemic and hemorrhagic strokes and are present in Alzheimer’s disease and related disorders (ADRD). CSVDs broadly fall into two classes: 1) amyloidal CVSD including sporadic and familial forms of cerebral amyloid angiopathy (CAA) and ADRD and 2) non-amyloidal CSVD involving common conditions such as hypertension, diabetes, arteriolosclerosis and a number of rare monogenic hereditary forms that includes cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is a rare autosomal recessive, inherited non-hypertensive CSVD that presents with early adult-onset VCID, gait disturbances, alopecia and spondylosis. Magnetic resonance imaging (MRI) studies of CARASIL patients show pronounced white matter (WM) changes including multiple lacunar infarcts, extensive WM lesions predominantly involving basal ganglia and brain stem and, in some cases, subcortical cerebral microbleeds. The WM lesions appear to result from small vessel damage characterized by extensive loss of cerebral arterial smooth muscle cells, loss of mural extracellular matrix and thickening and fragmentation of the internal elastic lamina. Although monogenic forms of CSVD are rare they share many clinical and neuropathological features with more common sporadic CSVDs including white matter damage, cerebral infarcts, cerebral bleeds and VCID. Previous studies have revealed that CARASIL results from specific mutations in the highly conserved high temperature requirement serine proteinase A1 (htra1) gene that markedly reduce or abolish the serine proteinase activity of Htra1 protein and believed to cause disruption of normal TGFb signaling that leads to smooth muscle degeneration and other cerebral arteriopathies in CARASIL patients. Mechanistic studies of CARASIL are hindered by the lack of effective animal models that faithfully recapitulate pathological features of human disease. Accordingly, the overall aim of this exploratory proposal is to generate and characterize a novel rat model of CARASIL by introducing a specific CARASIL mutation (R302Q) in the endogenous rat htra1 gene that will eliminate serine proteinase activity. To accomplish this overall goal, we propose the following three sets of experiments: First, we will conduct molecular and pathological characterization of a novel mutant ‘knock in’ rat model for CARASIL. Second, we will determine the consequences of emerging CSVD pathology on advanced cognitive and motor functions in the novel CARASIL rats. Lastly, we will perform neuroimaging studies to determine the impact of emerging CSVD on brain pathology as defined by MRI in the novel CARASIL rats. Successful completion of this work will provide a novel and unique animal model to the field of CSVD to more fully understand how this condition contributes to cerebral ar...