NRSA for David Braun: Vascular-associated Neuroinflammation in Alzheimer's Disease: Differential Effects on Disease Progression Modulated by Underlying Amyloid Burden

Current data suggest that up to 60% of Alzheimer’s disease (AD) patients present with comorbid cerebrovascular lesions, primarily cerebral amyloid angiopathy (CAA), infarcts, and microhemorrhages. Further, evidence indicates an important role for these in AD-associated cognitive decline: for example, the presence of vascular pathology additively increases the risk of dementia at every level of AD pathological burden. Additionally, the strongest non-genetic risk factors for AD are also vascular risk factors, and their presence in middle age additively increase the risk of later-life AD. Such considerations indicate that not only is it desirable to pursue therapeutic development in models with multiple pathologies, but also that treatment approaches addressing multiple pathologies at once may be more successful. This can be accomplished in two nonexclusive ways: with multi-drug strategies, or by targeting common mechanisms between pathologies. This proposal will focus on the latter approach. The overproduction of pro-inflammatory cytokines has been shown to have numerous deleterious effects and contribute mechanistically to both AD-type and vascular dementias, as well as vascular disease generally. This proposal will therefore test the central hypothesis that vascular and AD pathologies cause additive neuropathology and cognitive decline, and aberrant pro-inflammatory cytokine overproduction is a common pathological target in multifactorial AD of this type. Aim 1 will test the hypothesis that vascular and AD pathologies will lead to additive pathophysiological and functional deficits. We will use the well-established APPswe/PS1dE9 (APP/PS1) transgenic AD mouse model, put on a hyperhomocysteinemia (HHcy)-inducing diet (APP/PS1/HHcy) to induce CAA and microhemorrhages. In addition to standard behavioral, biochemical, and immunohistochemical characterization, these mice will also undergo longitudinal imaging using magnetic resonance imaging (MRI) to detect microhemorrhages, magnetic resonance spectroscopy (MRS) to detect alterations in glial and neuronal metabolites, and arterial spin labeling (ASL) to detect changes in cerebral blood flow (CBF). Aim 2 will use the same model and endpoints to test the hypothesis that aberrant pro-inflammatory cytokine production is a primary driver of cognitive decline in this comorbidity model. For these studies we will treat APP/PS1/HHcy mice in a chronic treatment paradigm with our novel anti-inflammatory compound MW151. These experiments will provide invaluable training in imaging techniques currently used in clinical trials, and position the applicant for a successful academic career in translational research. To ensure success, a career development plan has been developed, with specialty workshop participation, regular presentations of proposed research plans and results, participation in national and international scientific meetings, preparation of publications, and undergraduate mentoring. A successful mentor, expert committee of co-mentors, rich scientific environment, and an organized training plan assure that the applicant has optimal opportunities for scientific growth and development into an independent academic investigator.