The Golgi apparatus is a large structure in the cell that sets up transport of proteins to cell components by packaging and labeling the proteins to ensure they are sent to specific destinations. It is also involved in numerous other processes, such as the synthesis of some important proteins used by cell components, and far from all of these roles are fully cataloged and understood. It is known that rising levels of amyloid beta (Aβ) in and between brain cells characteristic of Alzheimer's disease harms the Golgi apparatus, and here researchers dig deep enough into this process to find a way to block that damage to see what happens:
Alzheimer's disease (AD) progresses inside the brain in a rising storm of cellular chaos as deposits of the toxic protein, amyloid-beta (Aβ), overwhelm neurons. An apparent 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. But is the destruction the Golgi a kind of collateral damage from the Aβ storm or is the loss of Golgi function itself part of the driving force behind Alzheimer's?
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).
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". By blocking cdk5 or its downstream target, that circuit can be broken or greatly slowed.