Year: 2009
Type: article
Abstract: The accumulation of amyloid beta (Aβ) peptides and β-amyloid plaques are central events in the development of Alzheimer's disease (AD). Aβ is produced by proteolysis of the amyloid precursor protein (APP). Trafficking and maturation of APP and its processing enzymes require proper functioning of the Golgi apparatus, a highly organized, stacked structure in the cell that plays a central role in protein trafficking, processing and maturation. It has been observed that the Golgi structure is fragmented abnormally in neurons from AD patients. However, the mechanisms underlying Golgi fragmentation and the consequences for APP trafficking and Aβ production are poorly understood. Using cell biological and biochemical methods we established for studying Golgi biogenesis, we sought to define Golgi defects in AD and determine the relationship between APP processing and Golgi perturbation. We used AD tissue culture (e.g. CHO cells) and transgenic mouse models in which both APPswe (APP “Swedish” mutation) and PS1ΔE9 (presenilin 1 with exon 9 deleted) are expressed. APP expression and Aβ accumulation were shown to induce Golgi fragmentation in both tissue culture and transgenic mouse models. Golgi fragmentation in turn was found to accelerate intracellular protein trafficking and alter glycosylation of cell surface membrane proteins. Fragmentation of the Golgi is mediated via phosphorylation of specific Golgi structural proteins (e.g. GRASP65) by kinases whose activity increases when Aβ accumulates. Taking advantage of new insights into the molecular regulation of Golgi integrity, we further demonstrate that Golgi structure can be rescued either by kinase inhibitors (e.g. roscovitine) or by overexpression of non-regulatable Golgi structural proteins (e.g. GRASP65). Ongoing studies will test whether the principal kinase inhibited by roscovitine is cdk5 and whether rescue of Golgi structure in the tissue culture model reduces Aβ production. Our results support a model of AD pathogenesis in which Aβ accumulation perturbs Golgi function, which in turn further augments Aβ production in the late secertory pathway. As rescue of the Golgi structure may reduce Aβ production and slow the amyloid cascade, the current results suggest potential novel therapeutic strategies in Alzheimer's disease.
Source: Alzheimer s & Dementia
Institution: University of Michigan
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2044436779