Impact of Wnt7a on Mast Cell-mediated inflammation associated with Alzheimer's Disease.

SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia and disability in the elderly and the sixth leading cause of death in the U.S. Signature AD pathology includes the presence of protein aggregation of neurotoxic amyloid-beta (Aβ) and tau tangles in the hippocampus. The only FDA-approved AD disease-

modifying drug, an antibody against Aβ (Aducanumab), has very limited benefit on cognition. Thus, there is an urgent need to develop additional therapies for AD. Interestingly, Aβ plaques are also found in healthy people, suggesting that Aβ alone is not sufficient to instigate AD. A recent study indicated that the strongest predictor for

AD is the presence of both neuroinflammation and Aβ plaques/tau tangles. The mast cell (MC) is a major type of immune cells that is increased in AD. MCs are critical for instigating and perpetuating inflammation. This because MCs can store large amounts of inflammatory mediators (e.g., TNFα, histamine, tryptase) in their granules, which can be released within minutes to hours upon activation, enabling

MCs to have a fast and strong impact on other immune cells. Direct evidence of MC’s importance in neuroinflammation in AD comes from the mouse study of infusing cromolyn, an inhibitor of MC activation, into the hippocampus, as well as from early-stage clinical trials, where MC inhibitor Masitinib led to cognitive benefits

in AD patients. However, regulators of MCs in the context of AD neuroinflammation remain largely elusive. Wnt7a is an important signaling molecule controlling neurogenesis in the hippocampus. However, little is known about the role of Wnt7a in MC-mediated inflammation during AD. The Parent R01 investigates Wnt7a as a critical

gatekeeper toward a propensity to develop osteoarthritis for its modulation of joint inflammation. In this Supplemental proposal, we will extend the investigation of the role of Wnt7a towards MC-mediated inflammation relevant to AD, capitalizing on the resources of the Parent R01 and expertise of an interdisciplinary team. In our

preliminary study, we discovered that neurotoxic Aβ1-42 significantly induced MC activation, and ectopic Wnt7a strongly inhibited MC activation. Thus, we hypothesize that Wnt7a inhibits MC activation induced by Aβ1-42, thereby reducing neuroinflammation associated with AD progression. We will test this hypothesis by investigating

whether Wnt7a is necessary and sufficient to inhibit amyloid β-induced MC activation and which pathways Wnt7a act through in this process. The novelty of this study lies in the investigation of the regulation of MC activation in the context of AD, an area that is largely unknown. It will have a profound and positive impact on the understanding AD pathogenesis. Since

MCs are strongly increased in osteoarthritis joints as well, this study will also fall within the scope of the parent R01 for investigating the role of Wnt7a on MC inflammation. Thus, this work is highly significant to both the fields of AD and osteoarthritis research.