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

Yung-Cheng Huang,Feng-Shiun Shie,Li-Jung Chao,Meng An Chien,Young-Ji Shiao,Chung-Chih Lin,Huey-Jen Tsay,Shu-Meng Hsu,Heng-Hsiang Yao,Hui-Wen Chen,Stephen D Ginsberg

doi:10.1371/journal.pone.0260966

Abstract

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 (Aβ) accumulation and cognitive impairment in AD transgenic mice. However, whether hyperglycemia reduce glial clearance of oligomeric amyloid-β (oAβ), the most neurotoxic Aβ aggregate, remains unclear. Mixed glial cultures simulating the coexistence of astrocytes and microglia in the neural microenvironment were established to investigate glial clearance of oAβ under normoglycemia and chronic hyperglycemia. Ramified microglia and low IL-1β release were observed in mixed glia cultures. In contrast, amoeboid-like microglia and higher IL-1β 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 oAβ 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 oAβ puncta internalized by microglia and astrocytes and decreased oAβ degradation kinetics. Furthermore, the lysosomal acidification and lysosomal hydrolysis activity of microglia and astrocytes were lower in HG with and without oAβ 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 oAβ degradation. Our study reveals diabetes-induced hyperglycemia hinders glial oAβ clearance and contributes to oAβ accumulation in AD pathogenesis.

Highlights

Alzheimer’s disease (AD) is an age-related neurodegenerative disease
Our findings provide evidence that sustained hyperglycemia impairs mitochondrial function and ATP production, which may contribute to lysosomal dysfunction, and in turn attenuate the degradation of internalized oligomeric Aβ (oAβ) in astrocytes and microglia
We and others have suggested that hyperglycemia and hyperlipidemia of prediabetes is associated with increased Aβ accumulation in amyloid precursor protein (APP)/PS1dE9 transgenic mice [15,16,17,18,19,20,21]

Summary

Introduction

Alzheimer’s disease (AD) is an age-related neurodegenerative disease. The accumulation of aggregated amyloid beta (Aβ) and neuroinflammation are one characteristic hallmark of AD. Among the various conformations of Aβ aggregates, oligomeric Aβ (oAβ) elicits the most synaptic toxicity [2, 3]. The levels of oAβ correlate with the degree of cognitive decline in patients with AD with mild cognitive impairment [4]. Sporadic and familial AD account for more than 95% and less than 5% of AD cases, respectively. In familial AD, accumulation of Aβ is mainly due to defective processing of mutant amyloid precursor protein [5]. The clearance of Aβ is decreased in the brain of patients with sporadic AD compared to normal individuals [6]

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Conclusion