Weston Brain Institute 2017 Advisor Fellow

There are no effective therapies available to prevent, cure, or slow the progression of Alzheimer’s disease (AD), and new therapeutic strategies are urgently needed. A major hurdle in clinical development is the diversity of comorbidities present in the AD patient population. “Pure” AD cases represent less than 20% of patients, and the most common pathological comorbidities are vascular in nature. Indeed, an exacerbation or unmasking of vascular pathology may be one contributor to the lack of clinical efficacy of amyloid-targeting immunotherapies, despite promising results in preclinical testing. To better predict the clinical utility of any given treatment, it is important to incorporate testing in multifactorial models of AD that are representative of a broader spectrum of AD patients. The present study will therefore test the efficacy of our small molecule AD drug candidate, MW151, in a mouse model of AD with comorbid cerebrovascular disease. MW151 is a novel, CNS-penetrant, orally bioavailable, small molecule drug candidate that selectively attenuates disease-induced cytokine up-regulation in the brain. Among the various animal models of CNS disorders where MW151 has demonstrated efficacy are two distinct AD mouse models. In both models, amyloid â (Aâ)-induced neuroinflammation, synaptic deficits and cognitive decline were attenuated by MW151 treatment. MW151 is currently in IND-enabling preclinical development as a promising non-amyloid targeted AD drug candidate. Whether such an approach remains effective in the context of AD-type pathology with comorbid vascular damage is currently unknown. To assess this, we will use the well-characterized transgenic APPswe/PS1dE9 mouse model of Aâ-overexpression. These mice will be placed on a diet to transiently induce hyperhomocysteinemia, leading to persistent vascular damage. This approach allows us to incorporate cerebrovascular pathology (including blood-brain barrier disruption, cerebral amyloidosis, and cerebral hypoperfusion) into a progressive model of Aâ-induced pathology, and determine whether targeting cytokine up-regulation with MW151 remains effective in such a situation, helping to define the appropriate patient population for eventual clinical testing.