White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer’s Disease

BySandra Ishkanes

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer’s. Age remains the greatest risk factor for Alzheimer’s and the prevalence of age-related late onset Alzheimer’s is greatest in females.

We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer’s risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration.

The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand.

Menopause is associated with decline in mitochondrial respiration, increased H2O2 production and shift to ketogenic metabolism in brain (Yao et al., 2010, Ding et al., 2013, Yin et al., 2015). These well established early age-related changes in mitochondrial function and shift to ketone body utilization in brain, are now linked to a mechanistic pathway that connects early decline in mitochondrial respiration and H2O2 production to activation of the cPLA2-sphingomyelinase pathway to catabolize myelin lipids resulting in white matter degeneration.

Perimenopause as a neurological transition state

BySandra Ishkanes

Estrogen-mediated regulation of the bioenergetic system: estrogen signalling supports and sustains glucose metabolism in the brain by regulating expression of glucose transporters, which results in increased glucose uptake, and by stimulating glucose metabolism, mitochondrial oxidative phosphorylation and ATP generation—collectively referred to as aerobic glycolysis. Glucose (1) is the primary metabolic fuel for the brain. Estrogen regulates the bioenergetic system in brain the through the estrogen receptors, GPER, ER-α and ER-β, and their activation of PI3K and downstream Akt and MAPK–ERK signalling pathways. When the glucose pathway is compromised, for example, during starvation, acetyl-CoA can be generated from ketone bodies via ketogenesis in the liver and transported through the blood to the brain through monocarboxylate transporters (2) or from fatty acid via β-oxidation (3).

During the perimenopausal transition, neuronal levels of glucose transporters decline, which is co-incident with the appearance of hypometabolism in the brain. The brain adapts to this decline in glucose availability by increasing reliance on ketone bodies as an alternative fuel to generate acetyl-CoA required for entry to the TCA cycle (4) and ultimately generation of ATP via complexes of the mitochondrial redox carriers (5).

Initially, ketone bodies are derived from the periphery by lipid metabolism in the liver. Depletion of peripheral sources of ketone bodies can result in metabolism of brain-derived fatty acids to generate ketone bodies via β-oxidation in glia cells (3).

Lupron, Brain Function, and the Keto Diet

BySandra Ishkanes

In the absence of estradiol, brain glucose transport diminishes significantly. This effectively starves the brain for energy inducing severe bioenergetic deficiencies with all of the concordant neuronal damage one might expect. The reduction in glucose affects the mitochondria severely. Recall that glucose is one of the major fuel substrates of the brain, particularly where the Western diet predominates. The decline of glucose transport, therefore, is significant, and alone, without any other changes to the mitochondria, elicits a cascade of deleterious reactions. Oxidative phosphorylation and associated enzymes are downregulated, ATP production wanes, and ultimately may initiate the deformation of the very shape of the mitochondria, as observed in the research cited above. The ensuing reduction of ATP starves the brain of critical energy but also induces a state of hypoxia with the mitochondria incapable of utilizing molecular oxygen. With that hypoxia, inflammatory pathways are initiated further cementing mitochondrial death spirals and associated neuronal damage.

Interestingly, this reduction in aerobic activity coincides with the emergence of a ketogenic phenotype. That is, with the loss of one fuel substrate, ketones become the dominant source of fuel and the associated enzyme machinery is upregulated. Unfortunately, the Western diet is highly dependent upon carbohydrates and so a woman experiencing this loss of estradiol is not likely to consume sufficient fats and proteins to effectively weather this shift. Nevertheless, it does provide an opportunity for recovery. What if women who have lost the ability to produce sufficient estradiol either because of surgically (oophorectomy) or chemically (Lupron and other GnRH analogs) induced menopause adopt a ketogenic diet? Could we maximize the preferred energy source of the post-menopausal brain and reduce the neurological symptoms?

Low Estrogen Exposure and/or Defective Estrogen Signaling Induces Disturbances in Glucose Uptake and Energy Expenditure

BySandra Ishkanes

Estradiol and its receptors are key players in the physiology and insulin production capacity of the β cells of pancreatic islets. Estradiol administration is associated with pancreatic islet hypertrophy and increased insulin release from the β cells in rats. Islet cells isolated from ovariectomized mice respond to glucose with a smaller insulin release than islet cells from intact mice.

After menopause, estrogen loss decreases the insulin secretion, which is transitorily compensated by its reduced elimination. An estrogen deficient milieu endangers the balanced glucose uptake and energy expenditure of skeletal muscles leading to insulin resistance.

Postmenopausal women never using HRT are obviously insulin resistant and exhibit increasing inclination to the associated comorbidities. With ageing, every year after menopause is associated with continuous estrogen loss and parallel advancing insulin resistance.

For women aged 55-65 years, weight gain and obesity are their major health risks. In postmenopausal women, deepening dysmetabolism, obesity and disturbance of male to female sexual steroid levels are associated with increased prevalence of metabolic syndrome, type 2 diabetes, cardiovascular disease and malignancies.

Estrogen: A master regulator of bioenergetic systems in the brain and body

BySandra Ishkanes

Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure.

During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer’s disease.

Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain.