Molecular Mechanisms of Axonal Pathology in Alzheimer’s Disease
MentorJaime Grutzendler, MD
Investigate the molecular and cellular mechanisms of axonal dystrophy formation in Alzheimer’s disease; examine reversibility of axonal dystrophy and whether this can restore normal axonal function. In Aim 1, I will study the proteins accumulated in axonal dystrophies in postmortem human AD brains by using proximity-labeling proteomic analysis, and uncover signaling pathways with potential relevance to axonal dystrophy formation and growth; in Aim 2, I will validate proteomic candidates identified in aim 1 in both postmortem human AD brains and AD-model mice; in Aim 3, I will examine the reversibility of axonal dystrophy by molecular manipulation of the PI3K/AKT/MTOR pathway or FDA approved drugs treatments in AD-model mice, and determine whether these improve axonal conduction in vivo.
Using proximity labeling proteomics, this study may be the first time to isolate and identify the proteome of axonal dystrophy, one of the three neuropathologic hallmarks in Alzheimer’s disease. This study will allow us to study the molecular and cellular mechanisms govern the axonal dystrophy formation. Utilization of both postmortem human AD brain specimens and AD-model mice will provide insights into the axonal dystrophy pathology in a complementary way. Given the accumulating failures of anti-amyloid drugs in AD clinical trials, identifying the molecular pathways that can prevent axonal dystrophy formation and ameliorate axon conduction deficits may provide novel therapeutic targets for AD, independent of amyloid removal. We believe information derived from these studies will suggest novel therapeutic targets for ameliorating axonal pathology in AD and will become a valuable resource for the scientific community.