DOPAMINE D2 RECEPTOR SIGNALING AS A REGULATOR OF NEUROVASCULAR FUNCTION IN AN ALZHEIMER’S DISEASE MOUSE MODEL

Alzheimer’s Disease (AD) is the leading type of dementia that is affecting over 55 million people worldwide. While amyloid-β and tau pathologies have long dominated AD research, recent findings highlight cerebral blood flow dysregulation and neurovascular dysfunction as early contributors to AD pathogenesis. These vascular abnormalities contribute to blood brain barrier breakdown, neuroinflammation, and cognitive decline, also known as vascular contributions to impairment and dementia (VCID). Dopamine and its receptors, particularly the D2 receptor (D2R), have been implicated in cerebrovascular regulation. Although little is known about D2R signaling in the context of VCID, D2R is highly prevalent in the brain. The goal of this study was to determine whether pharmacological activation of D2R can mitigate AD-induced neurovascular and behavioral dysfunction in the 3xTg-AD mouse model. Neurovascular coupling and blood-brain barrier integrity were assessed in vivo using two-photon microscopy. Tight junction proteins were quantified using capillary immunoassay ProteinSimple JESS. Cognitive and affective behaviors were measured using Y-maze, open field, novel object recognition test and forced swim test. Preliminary findings show that D2R activation improves neurovascular coupling, blood-brain barrier integrity and functional outcomes in 9-12 months 3xTg-AD mice. Collectively, this work establishes a mechanistic link between D2R signaling and cerebrovascular regulation in AD and insights into how D2R activation influences blood-brain barrier integrity, neurovascular coupling and behavioral outcomes.