Weston Brain Institute 2018 Advisor Support Agreement

Cerebrovascular pathology is a very common comorbidity with Alzheimer’s pathology. However, there is limited knowledge about the molecular mechanisms underlying the vascular contributions to cognitive impairment and dementia (VCID), or the mechanisms that link VCID and Alzheimer’s disease (AD) progression. A key mechanism that drives pathophysiology progression in many CNS disorders is dysregulated neuroinflammatory responses from innate immune cells in the brain, and chronic neuroinflammation is a common feature seen early in both VCID and AD progression. Based on our published and feasibility data, we hypothesize that vascular dysfunction in the context of Alzheimer pathology creates an enhanced neuroinflammatory state, that worsens the pathological outcomes. We focus on a particular form of neuroinflammation, overproduction of brain proinflammatory cytokines, that has been linked to synaptic damage, neurodegeneration, and cognitive decline in diverse CNS disorders, including AD and related dementias. Our therapeutic hypothesis is that selective attenuation of dysregulated cytokine responses at the appropriate disease progression time window is a viable therapeutic approach either as a monotherapy or, more likely, as a co-therapy for complex CNS diseases. To test our hypotheses, we will use the established hyperhomocysteinemia mouse model of cerebral small vessel disease to induce vascular injury in the APP/PS1 transgenic mouse. We will test the efficacy of our novel small molecule drug candidates that selectively suppress stressor-induced proinflammatory cytokine overproduction. Successful completion of these mechanistic and highly translational studies will provide insight into VCID/AD-driven neuroinflammatory responses in the brain, as well as provide evidence of whether selective targeting of the dysregulated cytokine response is a useful therapeutic strategy for AD/VCID.