Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production

Abstract

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/PS1ΔE9 transgenic mouse and tissue culture models. Our results show that accumulation of amyloid beta peptides (Aβ) leads to Golgi fragmentation. Further biochemistry and cell biology studies revealed that Golgi fragmentation in AD is caused by phosphorylation of Golgi structural proteins, such as GRASP65, which is induced by Aβ-triggered cyclin-dependent kinase-5 activation. Significantly, both inhibition of cyclin-dependent kinase-5 and expression of nonphosphorylatable GRASP65 mutants rescued the Golgi structure and reduced Aβ secretion by elevating α-cleavage of the amyloid precursor protein. Our study demonstrates a molecular mechanism for Golgi fragmentation and its effects on amyloid precursor protein trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment.Golgi stacking | APP processing | GRASP55 | amyloidogenic

Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice

“…Nevertheless, the demonstration that Golgi dysfunction causes neuronal loss in vivo, combined with the observation that neuronal loss and ataxia worsen with age upon loss of GM130, indicates that this process could, in principle, result in or at least contribute to the neurodegeneration that occurs in human disease. In support of this possibility, it has been shown that α-synuclein can perturb ER-to-Golgi traffic in Parkinson's disease models (49), and that the Aβ-fragment of APP that causes Alzheimer's disease, and the pathogenic form of ataxin-2 that causes SCA2, both disrupt Golgi organization (19,50). Hence, Golgi dysfunction and defective secretory trafficking, which could be attributable to a number of primary causes, may represent a significant pathogenic mechanism of neurodegenerative disease in humans.…”

Golgi apparatus in Alzheimer’s disease

“…In the pathogenic chain of AD, the further fragmentation of GA induced by Aβ peptide overproduction [29] may reasonably affect dendritic protein trafficking, which is essentialfor dendritic remodeling and arbor stability, since microtubules are closely associated with Golgi outpost and trafficking of vesicles and proteins towards the terminal dendritic branches and spines [30]. At the same time the Aβ peptide which is accumulated in multivesicular bodies [31], in association with mitochondrial dysfunction [32] may induce disruption of the synapses [31], a fact which is closely related with the cognitive decline in AD.…”

Structural and dynamic characterization of the Golgi Reassembly and Stacking Protein (GRASP) in solution

“…This result indicates that the unusual features observed for CnGRASP are not a consequence of uncompensated electrical charges along its amino acid sequence. We also observed that CnGRASP mutants intended to mimic site-directed phosphorylation in the SPR domain do not show disorder-to-order transitions, even though phosphorylation has proven important for breaking GRASP homo-dimerization and contributing to Golgi structural dynamics [52,53,57,60].…”

“…It was shown a correlation between β-amyloid peptides accumulation in the extracellular environment and the Golgi fragmentation caused by GRASP phosphorylation in Alzheimer disease [60]. In this process, the GRASP phosphorylation inhibition recovers the healthy Golgi phenotype and leads to a significant decrease of the β-amyloid peptides secretion, suggesting that the Golgi and GRASPs could be interesting targets in the pharmacologic strategies against Alzheimer disease [60].…”

“…It was shown a correlation between β-amyloid peptides accumulation in the extracellular environment and the Golgi fragmentation caused by GRASP phosphorylation in Alzheimer disease [60]. In this process, the GRASP phosphorylation inhibition recovers the healthy Golgi phenotype and leads to a significant decrease of the β-amyloid peptides secretion, suggesting that the Golgi and GRASPs could be interesting targets in the pharmacologic strategies against Alzheimer disease [60]. Furthermore, it has been also shown that GRASP65 is a critical downstream target for human immunodeficiency virus (HIV) to acquired immune deficiency syndrome (AIDS) progression in macrophages by inhibition of GRASP65-mediated cisternal linking [61,62].…”