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

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.

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

“…Individuals with diabetes that have higher peripheral fasting glucose levels also have higher brain glucose levels, which is suggested to alter brain Aβ processing and clearance ( Heikkila et al, 2009 ; Madhusudhanan et al, 2020 ). For instance, exposure of hyperglycemia in multiple cell types increases ROS levels ( Nishikawa and Araki, 2007 ; Shenouda et al, 2011 ; Lee et al, 2016 ), reduces mitochondrial function ( Nishikawa and Araki, 2007 ; Shenouda et al, 2011 ; Huang et al, 2022 ), reduces oligomeric Aβ clearance ( Huang et al, 2022 ), and increases BACE1 expression and Aβ production ( Lee et al, 2016 ). Interestingly, decreases in BACE1 have been shown to improve cellular glucose uptake ( Hamilton et al, 2014 ), which is impaired in both diabetes and AD.…”

RGS10 mitigates high glucose-induced microglial inflammation via the reactive oxidative stress pathway and enhances synuclein clearance in microglia

“…As the major phagocytes of the CNS, microglia play a critical role in clearing any aberrant protein species associated with neurodegenerative diseases ( Hickman et al, 2018 ). Both systemic inflammation and hyperglycemic conditions have been found to reduce the clearance capacity of microglia in preclinical AD models and mixed glial cultures, respectively, ( Tejera et al, 2019 ; Xie et al, 2021 ; Huang et al, 2022 ). Furthermore, both systemic inflammation and hyperglycemia have shown to exacerbate α-syn aggregation mouse models ( Kim et al, 2022 ; Lv et al, 2022 ).…”

Neonatal Rat Glia Cultured in Physiological Normoxia for Modeling Neuropathological Conditions In Vitro

“…[ 94 , 95 ]. The neonatal glial cultures are also useful for studies on neurodegenerative diseases, including PD [ 96 , 97 ], AD [ 98 , 99 , 100 , 101 ], MS [ 102 , 103 ], or triggered by exposure to environmental toxicants and pollution [ 104 , 105 , 106 ]. Culturing cells in oxygen concentration is relevant for that present in the nervous tissue, and the elimination of serum and other supplements create opportunities to eliminate microenvironmental clues, potentially affecting investigated processes or modulating drug effectiveness.…”