Rescuing the golgi puts brakes on Alzheimer’s progress

The unsurprising part of the answer was that rising levels of Aβ do lead directly to Golgi fragmentation by activating a cell cycle kinase, cdk5. The surprising part of the answer was that Golgi function can be rescued by blocking cdk5 or shielding its downstream target protein in the Golgi, GRASP65. The even more surprising answer was that rescuing the Golgi reduced Aβ accumulation significantly, apparently by re-opening a normal protein degradation pathway for the amyloid precursor protein (APP). To Wang et al, this suggested an entirely new line of attack for drugs hoping to slow AD progression.

Speaking at the ASCB/IFCB Meeting in Philadelphia, the researchers now say that Golgi fragmentation is in itself a major -- and until now an unrecognized -- mechanism through which Aβ extends its toxic effects. They believe that as Aβ accumulation rises, damage to the Golgi increases, which in turn accelerates APP trafficking, which in turn increases Aβ production. This is a classic "deleterious feedback circuit," they say. By blocking cdk5 or its downstream target, that circuit can be broken or greatly slowed. "Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment," the Michigan researchers report.