ABSTRACT Alzheimer’s disease (AD) is a devastating and incurable disease afflicting over millions of people worldwide. Its pathogenesis is widely believed to be driven by the production and deposition of the β-amyloid peptide (Aβ), causing disturbances in synaptic activity and neuronal death. Multiple studies have provided strong evidence relating these effects to increased oxidative stress and to calcium imbalance resulting from aberrant activity of calcium-permeable cation channels. Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable nonselective cation channel most highly expressed in the CNS, has been implicated in Alzheimer’s disease via both amyloid-induced and oxidative stress-induced toxicity. Therefore, the TRPM2 channel is a promising therapeutic target for the neurovascular impairment associated with AD and related diseases. My current R01 grant (R01NS111031) focuses on structural and functional studies of the TRPM2 channel to reveal its basic gating mechanism using single-particle electron microscopy, x-ray crystallography, and patch- clamp electrophysiology. The redox-sensitive TRPM2 channel has been proven to be activated by Aβ peptide and oxidative stress, which results in cytosolic calcium overload and causes neuron death in AD. I propose to study the relationship of TRPM2 activity with Aβ and oxidative stress in this Alzheimer’s-Focused Administrative Supplement NOT-AG-21-018. We believe that TRPM2, an important but understudied target in AD, fits perfectly into the category of the Alzheimer’s-Focused Administrative Supplement Fund which would allow us to generate the preliminary datasets needed to propel this unorthodox, high-risk-high-reward research program forward.