Validating the Receptor PILRA as an Alzheimer's Therapeutic Target

Our project will test whether PILRA protein is a valid therapeutic target for Alzheimer’s disease (AD) by learning whether PILRA suppresses microglial TREM2 signaling, phagocytosis, and AD protection.

The emerging landscape of Alzheimer’s therapeutics includes drugs intended to promote the protective functions of microglia, the brain’s immune cells. The majority of these therapeutics seek to directly activate TREM2, a key receptor for microglial activation and healthy CNS tissue maintenance. In this proposal, we explore the therapeutic potential of blocking microglial checkpoint proteins as an indirect way of enabling more robust TREM2 function at sites of microglial activation, which may be safer than chronic activation of all microglia (and possibly osteoclasts/macrophages).

While several companies are developing TREM2 agonists to promote the protective activation of microglial cells in Alzheimer’s disease (AD) brains, another approach to achieve a similar outcome is to block the function of immune checkpoint proteins. PILRA and CD33 are microglia-expressed checkpoint proteins associated with AD risk, but only CD33 is being targeted in clinical trials. This study will explore the hypothesis that the role of PILRA in AD pathogenesis is more substantial than the role of CD33, and we will establish an animal AD model for pharmacological targeting of human PILRA.

If our hypotheses are true, our study will benefit the AD research field in several ways. We will validate PILRA G78R as the causal genetic variant responsible for the association of the ZCWPW1 locus with AD protection; we will provide a cellular mechanism for understanding how PILRA function contributes to AD pathogenesis; we will validate PILRA as a potential therapeutic target for preventing or delaying AD progression; and we will establish an animal AD model for future pharmacological targeting of human PILRA function. This may benefit the general public by leading to new AD therapies.