Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing

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Abstract

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

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Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Aaron M Koenig, Shannon L. Macauley-Rambach, Zoe Arvanitakis … (2018)

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

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Lactate in the brain: from metabolic end-product to signalling molecule

Pierre Magistretti, Igor Allaman (2018)

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Myelination of the nervous system: mechanisms and functions.

Klaus-Armin Nave, Hauke B. Werner (2014)

Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology. However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions. In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath. In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages. Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors. The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models. Thus, myelinating cells serve a key role in preserving the connectivity and functions of a healthy nervous system.