Reduced mitochondria membrane potential and lysosomal acidification are associated with decreased oligomeric A[beta] degradation induced by hyperglycemia: A study of mixed glia cultures

• Published in: PloS one Vol. 17; no. 1; p. e0260966
• Main Authors: Huang, Yung-Cheng, Hsu, Shu-Meng, Shie, Feng-Shiun, Shiao, Young-Ji, Chao, Li-Jung, Chen, Hui-Wen, Yao, Heng-Hsiang, Chien, Meng An, Lin, Chung-Chih, Tsay, Huey-Jen
• Format: Journal Article
• Language: English
• Published: Public Library of Science 24.01.2022
• Subjects: Alzheimer's disease; Amyloid beta-protein; Chemical properties; Complications and side effects; Health aspects; Hyperglycemia; Lysosomes; Membrane potentials; Mitochondrial membranes; Proteolysis; Risk factors; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0260966

Diabetes is a risk factor for Alzheimer's disease (AD), a chronic neurodegenerative disease. We and others have shown prediabetes, including hyperglycemia and obesity induced by high fat and high sucrose diets, is associated with exacerbated amyloid beta (A[beta]) accumulation and cognitive impairment in AD transgenic mice. However, whether hyperglycemia reduce glial clearance of oligomeric amyloid-[beta] (oA[beta]), the most neurotoxic A[beta] aggregate, remains unclear. Mixed glial cultures simulating the coexistence of astrocytes and microglia in the neural microenvironment were established to investigate glial clearance of oA[beta] under normoglycemia and chronic hyperglycemia. Ramified microglia and low IL-1[beta] release were observed in mixed glia cultures. In contrast, amoeboid-like microglia and higher IL-1[beta] release were observed in primary microglia cultures. APPswe/PS1dE9 transgenic mice are a commonly used AD mouse model. Microglia close to senile plaques in APPswe/PS1dE9 transgenic mice exposed to normoglycemia or chronic hyperglycemia exhibited an amoeboid-like morphology; other microglia were ramified. Therefore, mixed glia cultures reproduce the in vivo ramified microglial morphology. To investigate the impact of sustained high-glucose conditions on glial oA[beta] clearance, mixed glia were cultured in media containing 5.5 mM glucose (normal glucose, NG) or 25 mM glucose (high glucose, HG) for 16 days. Compared to NG, HG reduced the steady-state level of oA[beta] puncta internalized by microglia and astrocytes and decreased oA[beta] degradation kinetics. Furthermore, the lysosomal acidification and lysosomal hydrolysis activity of microglia and astrocytes were lower in HG with and without oA[beta] treatment than NG. Moreover, HG reduced mitochondrial membrane potential and ATP levels in mixed glia, which can lead to reduced lysosomal function. Overall, continuous high glucose reduces microglial and astrocytic ATP production and lysosome activity which may lead to decreased glial oA[beta] degradation. Our study reveals diabetes-induced hyperglycemia hinders glial oA[beta] clearance and contributes to oA[beta] accumulation in AD pathogenesis.