Biology

Dr. Swetha Gowrishankar
Yale University, USA

Lysosome-filled axonal swellings are a major, but poorly understood feature of Alzheimer’s disease amyloid plaques. It is not clear what causes these axonal lysosomes to accumulate at amyloid plaques or whether they contribute to the disease pathology.  Our previous characterization of these lysosomes at amyloid plaques led us to propose a model where these axonal lysosomes accumulate due to a local defect in their retrograde transport and maturation and represent pathologically meaningful sites of Aβ production [1]. To test this hypothesis, we developed mouse genetic strategies to alter axonal lysosome abundance and examine the impact on amyloid plaque pathology. To this end, we identified JNK-interacting protein-3 (JIP3) as a candidate for regulating axonal lysosome abundance and validated such a function through extensive cell biological characterization of JIP3 KO mouse neurons. These efforts revealed that JIP3 is an important regulator of the transport, abundance and maturation state of axonal lysosomes. Furthermore, we observed multiple similarities between the axonal lysosomes that accumulate in JIP3 KO neurons and those that build up around amyloid plaques. This includes a build up of amyloid precursor protein (APP), and its processing enzymes- β-secretase (BACE1) and presenilin 2 (PSEN2). We detected significantly elevated Aβ levels in the JIP3 KO neurons, consistent with the hypothesis that the build up of the above-mentioned proteins leads to increased processing of APP into Aβ peptides, in the accumulating axonal lysosomes. Finally, our examination of the in vivo relationship between JIP3-dependent axonal transport of lysosomes and amyloid plaque pathology revealed that loss of JIP3 was accompanied by an increase in soluble Aβ levels, amyloid plaque size, abundance and axonal dystrophy [2].  These results collectively support a model wherein efficient retrograde axonal lysosome transport and maturation acts as a negative regulator of APP processing and the development of amyloid plaque pathology.