RT Journal Article
SR Electronic
T1 Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 618496
DO 10.1101/618496
A1 Yasir H. Qureshi
A1 Diego E. Berman
A1 Ronald L. Klein
A1 Vivek M. Patel
A1 Sabrina Simoes
A1 Suvarnambiga Kannan
A1 Rebecca Cox
A1 Samuel D Waksal
A1 Beth Stevens
A1 Gregory A. Petsko
A1 Scott A. Small
YR 2019
UL http://biorxiv.org/content/early/2019/05/15/618496.abstract
AB Retromer has emerged as a master conductor of endosomal trafficking, and VPS35 and other retromer-related proteins are found to be deficient in late-onset Alzheimer’s disease (AD). Depleting VPS35 in neurons impairs retromer function, affecting for example the trafficking of the amyloid-precursor protein (APP) and the glutamate receptor GluA1. Whether VPS35 repletion, after chronic in vivo depletion, can rescue these impairments remains unknown. Here we set out to address this question by using a viral vector approach for VPS35 repletion. First, we completed a series of studies using neuronal cultures in order to optimize AAV9-VPS35 delivery, and to understand how exogenous VPS35 expression affects its endogenous levels as well as its binding to other retromer proteins. Next, we completed a series of studies in wildtype mice to determine the optimum protocol for in vivo delivery of AAV9-VPS35 to the hippocampus. We relied on this information to deliver AAV9-VPS35 to the hippocampus of mice genetically engineered to have chronic, neuronal-selective, VPS35 depletion. VPS35 repletion in the hippocampus was found to normalize APP cleavage and to restore glutamate receptor levels. Unexpectedly, chronic VPS35 depletion in neurons caused glial activation, similar to the pattern observed in AD, which was also partially normalized by VPS35 repletion. Taken together, these studies strengthen the mechanistic link between retromer and AD, and have therapeutic implications.