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 (Aß) and tau tangles in the hippocampus. The only FDA-approved AD disease-
modifying drug, an antibody against Aß (Aducanumab), has very limited benefit on cognition. Thus, there is an
urgent need to develop additional therapies for AD. Interestingly, Aß plaques are also found in healthy people,
suggesting that Aß alone is not sufficient to instigate AD. A recent study indicated that the strongest predictor for
AD is the presence of both neuroinflammation and Aß 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., TNFa,
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 Aß1-42 significantly induced MC activation, and ectopic Wnt7a
strongly inhibited MC activation. Thus, we hypothesize that Wnt7a inhibits MC activation induced by Aß1-42,
thereby reducing neuroinflammation associated with AD progression. We will test this hypothesis by investigating
whether Wnt7a is necessary and sufficient to inhibit amyloid ß-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.