ABSTRACT:

Type 2 diabetes is associated with increased Alzheimer’s disease risk and brain beta amyloid (Aβ) burden, suggesting an underlying mechanistic relationship between Alzheimer’s disease and type 2 diabetes. Animal studies show exercise reduces levels of brain Aβ and tau, and while human studies are somewhat limited, some studies have reported physical activity is associated with lower brain Aβ and tau levels. Exercise has well established links to reductions in insulin resistance; thus, as physical activity can impact both insulin resistance and Alzheimer’s disease pathology and/or biomarkers, it is reasonable to hypothesise that a mediating relationship may exist. The objective of this review was to identify what evidence exists that examines the association between insulin, physical activity, Aβ and tau in research conducted on animal models and in human cohorts. We specifically aimed to identify whether insulin resistance has a mediating role in the relationship between physical activity and Aβ and tau.

Slee, M. G., J. Scotney, S. R. Rainey-Smith, K. I. Erickson, H. R. Sohrabi, G. Verdile, and B. M. Brown. 2026. Insulin resistance as a mediator of physical activity's effects on beta-amyloid accumulation and tau phosphorylation: A scoping review. Ageing Research Reviews 114

ABSTRACT:
Inorganic nitrate plays a crucial role in the regulation of cerebral blood flow and neurotransmission through its conversion to nitric oxide (NO). Astrocytes are star-shaped glial cells and contribute to maintain the blood-brain barrier integrity, regulate neuronal metabolism, support synaptic plasticity and facilitate neurovascular coupling. Inorganic nitrate widely distributed through all organs, with main reservoirs in skeletomuscular and skin tissues. These reserves are easily accessible via bloodstream and processed into nitrite and NO mainly in liver. Processing nitrate/nitrite into NO at organ with main glycogen stores, could suggest an evolutionary coordination between energy metabolism and NO generating pathways. Such spatial arrangement may facilitate the synchronised mobilisation during periods of enhanced metabolic demand, optimising both fuel utilisation and vascular response and assuring optimal fuel distribution. Astrocytes store glycogen in the brain, which support neuronal metabolism during periods of increased neural activity and hypoglycaemia.
This review explores the hypothesis that inorganic nitrate may be stored alongside glycogen in astrocytes and serve as critical reserves for NO production in the brain, particularly during hypoxic conditions. We examine the emerging evidence that astrocytes serve as key mediators in this alternative nitrate-nitrite-NO pathway, potentially influencing cerebrovascular regulation, neuronal energetics, and cognitive function. The integration of findings across molecular, cellular, and systems neuroscience offers new perspectives on how inorganic nitrate intake might support brain metabolism and could inform both preventive strategies and therapeutic interventions for neuro-degenerative disorders such as age-related dementia, stroke or Parkinson's Disease.

Siervo, M., G. Verdile, and B. Piknova. 2025. Inorganic nitrate stores, astrocyte metabolism and brain health: An emerging paradigm.Nitric Oxide: Biology and Chemistry 158: 76-81.