Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD. [Display omitted] •A decline in brain glucose levels and metabolism is pathologically linked to AD and dementia.•Insulin resistance and mitochondrial dysfunction are implicated in classic plaque and tangle pathologies of AD.•Aberrant IRS/PI3K/Akt/AMPK signaling and abnormal GLUT activities are directly linked to the etiology of neurodegeneration.•Defective glucose metabolism-induced polyol activation, AGEs accumulation and oxidative stress contribute to AD pathogenesis.•Abnormal glucose metabolism endorses cerebral autophagy/mitophagy dysregulation by hampering lysosome-mitochondrial functions.