Investigating Golgi Fragmentation in Alzheimer?s Disease

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

? DESCRIPTION (provided by applicant): Amyloid beta (A?) peptide accumulation and amyloid formation are central events that mediate neurodegeneration in Alzheimer's disease (AD). A? is produced by proteolysis of the amyloid precursor protein (APP). Trafficking and maturation of APP and its processing enzymes requires proper functioning of the Golgi apparatus, which depends on the highly ordered stacked structure. The structure of the Golgi apparatus is fragmented in the neurons of AD patient's brain. However, the relationship between Golgi fragmentation and neurodegeneration in AD is largely unknown. Preliminary studies in AD transgenic mouse and tissue culture models suggests that A?-induced Golgi fragmentation disrupts APP trafficking and processing, while restoring Golgi morphology rescues these defects. These results suggest that Golgi fragmentation is an important mechanism through which A? may exert its toxic effects. A potential unrecognized source of A? toxicity may be that it compromises Golgi integrity and perturbs trafficking and processing of cell-surface proteins that are essential for neuronal function and viability. Therefore, we hypothesize that A?-induced Golgi fragmentation disrupts trafficking and processing of APP and essential cell-surface proteins, which increases A? production and compromises the function and viability of neurons in AD. The objective of this proposal is to determine the role of A?-induced Golgi fragmentation in AD development, evaluate the impact of Golgi fragmentation and restoration on trafficking of APP and cell-surface proteins, and identify novel pathways that mediate neurodegeneration in AD. Accomplishing the proposed aims will help clarify the relationship between Golgi fragmentation, enhanced A? production, and neurodegeneration in AD. Identifying new pathways that mediate neurotoxicity that are regulated by Golgi morphology would warrant further investigation into the molecular mechanism of Golgi fragmentation as a strategy for preventing neurodegeneration in AD and perhaps other neurodegenerative disorders.