Axonal Lysosome dysfunction in Alzheimer’s disease

Excess levels of the amyloid ß (Aß) peptide and the aggregation of the Aß peptide within extracellular amyloid plaques are defining features of Alzheimer’s disease brain pathology. A poorly understood aspect of these amyloid plaques is the massive abundance of lysosomes that selectively accumulate within swollen neuronal axons that pass close to them. We use mouse models of Alzheimer’s disease to investigate the mechanisms that give rise to the abnormal abundance and localization of lysosomes in Alzheimer’s disease neurons with the expectation that such studies will enhance understanding of how neurons regulate lysosome abundance and localization and how modulation of lysosome function could have therapeutic benefits in the treatment of Alzheimer’s disease. This line of investigation is supported by our discovery that the impaired axonal transport of lysosomes in JIP3 (aka MAPK8IP3) promotes amyloidogenic processing of APP and results in more soluble Aß and more amyloid plaques. ln addition to mouse models, we also take advantage of human induced pluripotent stem cells (iPSCs) and neurons derived from them to study axonal transport mechanisms that converge on lysosomes and Alzheimer's disease mechanisms.