Cerebrovascular accumulation of the amyloid b-protein (Ab), a condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that is prevalent in the elderly, a prominent comorbidity of patients with Alzheimer?s disease (AD) and an important driver of vascular cognitive impairment and dementia (VCID). Despite the growing recognition of the contribution of CAA to dementia in AD and in VCID, there currently exists no effective therapeutic interventions for this condition. CAA can uniquely contribute to the cognitive decline in VCID and AD in several manners. For example, in response to deposited fibrillar Ab in CAA cognitive impairment is worsened by a chronic state of perivascular neuroinflammation and activation that is characterized by reactive astrocytes and activated microglia and endothelial cells that can produce thrombin, pro-inflammatory cytokines and chemokines, and reactive oxygen and nitrogen species. Also, the increase in perivascular expression and activation of certain proteolytic enzymes, including thrombin, can contribute to microinfarcts, disruption of vessel wall integrity and cerebral hemorrhage, all highly deleterious manifestations of the disease. Thus, perivascular neuroinflammation, vascular activation, thrombosis and hemorrhage associated with cerebral vascular amyloid can all be linked to thrombin, which represents a potential therapeutic target to treat CAA/VCID. Based on our preclinical work in AD mouse models we now propose to test the hypothesis that thrombin-mediated vascular activation, neuroinflammation and thrombosis is a central mechanism contributing to small vessel CAA pathology in the brain and that inhibiting thrombin will improve clinically relevant CAA pathological and VCID-associated endpoints. To test our hypothesis, we first propose to test if early and long-term administration of dabigatran is effective as a preventative treatment to reduce CAA pathology and associated VCID. Specifically, we will test if long term treatment with dabigatran reduces CAA, perivascular neuroinflammation, small vessel occlusions, cerebral microbleeds and improves cognitive performance in a novel and unique transgenic rat model of small vessel CAA. Second, we propose to test if administration of dabigatran during later stage disease is effective as an intervention to reduce CAA pathology and associated VCID. Specifically, we will test if shorter term treatment with dabigatran during later stages in the disease can lower CAA-related perivascular neuroinflammation, small vessel occlusions, cerebral microbleeds and improve cognitive performance in our transgenic rat model of small vessel CAA. Successful outcomes in these exploratory studies will pave the way for future studies to understand the precise beneficial mechanisms of dabigatran. This will complement our ongoing clinical studies of dabigatran treatment in early stage AD and could provide a needed therapeutic agent for CAA related vasculopathy and VCID.
Cerebrovascular accumulation of the amyloid b-protein, a condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease in the elderly, an important driver of vascular cognitive impairment and dementia (VCID) and a prominent comorbidity of patients with Alzheimer?s disease. Currently, effective therapeutic agents to treat CAA/VCID do not exist. The purpose of this project is to perform preclinical studies to determine if targeting the multifunctional proteinase thrombin can reduce CAA pathology and VCID.
