Rescuing the Golgi put brakes on Alzheimer's progression
American Society for Cell Biology
eurekalert.org
Alzheimer's disease (AD) progresses inside the brain in a rising storm of cellular chaos as deposits of the toxic protein, amyloid-beta (Aß), overwhelm neurons. An apparent side effect of accumulating Aß 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 Aß. But is the destruction the Golgi a kind of collateral damage from the Aß storm or is the loss of Golgi function itself part of the driving force behind Alzheimer's? This was the question for Yanzhuang Wang, Gunjan Joshi, and colleagues at the University of Michigan, Ann Arbor, as they set out to uncover the mechanism damaging the Golgi, using a transgenic mouse and tissue culture models of AD to look at what was going on.
The unsurprising part of the answer was that rising levels of Aß 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 Aß 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 Aß extends its toxic effects. They believe that as Aß accumulation rises, damage to the Golgi increases, which in turn accelerates APP trafficking, which in turn increases Aß 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.
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Golgi defects in Alzheimer's disease G. Joshi1, Y. Chi1, Z. Huang1, Y. Wang1; 1Dept. of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI
Poster 2103
Board Number: B626
Golgi defects in Alzheimer’s disease.
G. Joshi1, Y. Chi1, Z. Huang1, Y. Wang1;
1Dept. of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI
Golgi fragmentation occurs in neurons of patients with Alzheimer’s disease (AD), but the underlying molecular mechanism causing the defects and the subsequent effects on disease development remain unknown. In this study, we examined the Golgi structure in APPswe/PS1?E9 transgenic mouse and tissue culture models. Our results suggest that Aß accumulation leads to Golgi fragmentation by activating cdk5, which in turn phosphorylates GRASP65 and perhaps other key proteins critical for maintaining Golgi morphology. Significantly, rescue of Golgi structural defects by inhibiting cdk5 or by expressing nonphosphorylatable mutants of GRASP65 reduces Aß secretion by elevating nonamyloidogenic APP cleavage. These results reveal Golgi fragmentation as an important mechanism through which Aß may exert its toxic effects. A major potential unrecognized source of Aß toxicity may be that it compromises Golgi integrity and perturbs the proper trafficking and processing of many proteins essential for neuronal function. We hypothesize that in AD, Aß accumulation promotes Golgi defects, which in turn accelerate APP trafficking and Aß production; this deleterious feedback circuit would impair the integrity of the secretory pathway and thereby compromise neuronal cell function. 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. |
