Alzheimer's disease progresses inside the brain as deposits of the toxic protein amyloid-beta (Aβ),overwhelm neurons. A side effect of accumulating Aβ in neurons is the fragmentation of the Golgi apparatus, the part of the cell involved in packaging and sorting protein cargo including the precursor of Aβ. Or it may be the other way around and loss of Golgi function is a driving force behind Alzheimer's.

Yanzhuang Wang, Gunjan Joshi, and colleagues at the University of Michigan, Ann Arbor, set out to uncover the mechanism damaging the Golgi using a transgenic mouse and tissue culture models of 
Alzheimer's disease
to look at what was going on. 

The unsurprising part is that rising levels of Aβ do lead directly to Golgi fragmentation by activating a cell cycle kinase, cdk5. The surprising part is 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 Alzheimer's disease, suggesting Golgi as a potential drug target for AD treatment," the Michigan researchers report.