Project Summary: Dysfunction of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is implicated in the physiopathology of neurological disorders such as schizophrenia and depression, and neurodegenerative diseases, including Alzheimer’s disease (AD) and its related dementias. A role for AMPAR in AD was also suggested by the observation that its expression and activity was significantly altered in areas of inflammation in AD patients and decreased AMPAR expression occurred at the onset of AD. Pharmacological modulation of AMPAR prevents excessive neuronal activation, representing an attractive therapeutic approach for AD treatment. Quantification of AMPAR in the living brain, particularly in the AD brain, would enable the assessment of changes and distribution during disease prognosis, which will provide valuable information for AMPAR-targeted AD neurotherapeutics. As a non-invasive imaging probe, positron emission tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable AMPAR probe would substantially improve our understanding of AMPAR-based ionotropic glutamate signaling under normal and AD conditions otherwise inaccessible by ex vivo (destructive) analysis. The PI has utilized several PET ligands to measure transmembrane AMPA regulatory proteins activity and possible aberrant ionotropic glutamate system function in his parent R01 grant. In this AD-focused administrative supplement application, we aim to evaluate these PET ligands for their ability to non-invasively track transmembrane AMPA regulatory proteins changes in vivo to monitor AD progression in two transgenic mouse models, followed by ex vivo biological validation studies in AD mice. The goal of this administrative supplement is to assess the utility of AMPAR-orientated PET ligands as functional index for AD prognosis and test the specificity and sensitivity of AMPAR- related protein changes between normal and AD disease states. Overall impact: This work will represent a novel PET biomarker study measuring changes of subtype AMPAR (transmembrane AMPA regulatory proteins) in the AD progression. We expect that this proposed work will not only help us to differentiate symptomatic from true mechanistic response via PET imaging, but also provide guidance for AMPAR-based interventions to improve quality of life of AD patients.