Abstract
Metabolic insufficiency and neuronal dysfunction occur in normal aging but is exaggerated in dementia and Alzheimer’s disease (AD). Metabolic insufficiency includes factors important for both substrate supply and utilization in the brain. Metabolic insufficiency occurs through a number of serial mechanisms, particularly changes in cerebrovascular supply through blood vessel abnormalities (ie, small and large vessel vasculopathy, stroke), alterations in neurovascular coupling providing dynamic blood flow supply in relation to neuronal demand, abnormalities in blood brain barrier including decreased glucose and amino acid transport, altered glymphatic flow in terms of substrate supply across the extracellular space to cells and drainage into CSF of metabolites, impaired transport into cells, and abnormal intracellular metabolism with more reliance on glycolysis and less on mitochondrial function. Recent studies have confirmed abnormal neurovascular coupling in a mouse model of AD in response to metabolic challenges, but the supply chain from the vascular system into neurons is disrupted much earlier in dementia than in equivalently aged individuals, contributing to the progressive neuronal degeneration and cognitive dysfunction associated with dementia. We discuss several metabolic treatment approaches, but these depend on characterizing patients as to who would benefit the most. Surrogate biomarkers of metabolism are being developed to include dynamic estimates of neuronal demand, sufficiency of neurovascular coupling, and glymphatic flow to supplement traditional static measurements. These surrogate biomarkers could be used to gauge efficacy of metabolic treatments in slowing down or modifying dementia time course.
Highlights
There are multiple proposed underlying hypotheses of Alzheimer’s disease (AD) and related therapeutic strategies, in relation to normal aging [1, 2]
Even short periods of inadequate substrate supply during high demand may lead to hypoglycemia or hypoxia and insufficient energetic capability, accelerating AD changes [21, 30, 49, 50].Covert hyperexcitability, excessive neuronal activity, and reduced metabolism for glutamate uptake may contribute to a greater metabolic need that may be unmatched by supply [51], as well as enhanced glutamate and excitotoxicity [45, 52]
The overall finding of these studies was that CVN-AD results showed premature aging effects compared to the age matched controls [16]. These novel results show a significant reduction in neurovascular coupling in response to robust metabolic demand in middle-aged and aged CVN-AD mice compared to age-matched controls, confirming that a significant aspect of metabolic deficiency in AD may arise from insufficient, dynamic substrate delivery to the brain [28]
Summary
Low glucose metabolism occurs pervasively in early AD [26, 37]. Possible factors include altered blood vessels and stroke [6], insufficient neurovascular coupling and/or inadequate glucose delivery to capillaries [7, 28], reduced glucose transport across the blood brain barrier [38], as well as intrinsic changes in metabolism within neurons, such as changes in oxidative phosphorylation [20, 39] and mechanistic target of rapamycin (mTor) and other regulatory alterations [40,41,42]. Even short periods of inadequate substrate supply during high demand may lead to hypoglycemia or hypoxia and insufficient energetic capability, accelerating AD changes [21, 30, 49, 50].Covert hyperexcitability, excessive neuronal activity, and reduced metabolism for glutamate uptake may contribute to a greater metabolic need that may be unmatched by supply [51], as well as enhanced glutamate and excitotoxicity [45, 52] Many of these factors are shown in more detail, which highlights more details of substrate movement from blood vessels into cells, many of which change in AD and aging [21]. 0.5-1.5 mM and both vary dynamically with neuronal activity
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