Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism

(New study)
http://www.jneurosci.org/content/early/2018/07/02/JNEUROSCI.2262-17.2018

Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism

Abstract

Humans possess three genetic isoforms of apolipoprotein E (ApoE)—ApoE2, ApoE3 and ApoE4—that confer differential risk for Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. This study sought to investigate the impact of human ApoE isoforms on brain energy metabolism, an area significantly perturbed in preclinical AD. A TaqMan custom array was performed to examine the expression of a total of 43 genes involved in glucose and ketone body transport and metabolism focusing on cytosolic oxidation in human ApoE gene-targeted replacement (hApoE-TR) female mice. Consistent with our previous findings, brains expressing ApoE2 exhibited the most robust profile, whereas brains expressing ApoE4 displayed the most deficient profile on the uptake and metabolism of glucose, the primary fuel for the brain. Specifically, the three ApoE brains differed significantly in facilitated glucose transporters, which mediate the entry of glucose into neurons, and hexokinases, which act as the “gateway enzyme” in glucose metabolism. Interestingly, on the uptake and metabolism of ketone bodies, the secondary energy source for the brain, ApoE2 and ApoE4 brains showed a similar level of robustness, whereas ApoE3 brains presented a relatively deficient profile. Further, ingenuity pathway analysis (IPA) indicated that the PPAR-γ/PGC-1α signaling pathway could be activated in the ApoE2 brain and inhibited in the ApoE4 brain. Notably, PGC-1α overexpression ameliorated ApoE4-induced deficits in glycolysis and mitochondrial respiration. Overall, our data provide additional evidence that human ApoE isoforms differentially modulate brain bioenergetic metabolism, which could serve as a potential mechanism contributing to their discrete risk impact in AD.

SIGNIFICANCE STATEMENT

We uncovered hexokinase as a key cytosolic point in the glucose metabolism that is differentially modulated by the three ApoE genotypes. The differences in hexokinase expression and activity exhibited in the three ApoE brains may underlie their distinct impact on brain glucose utilization and further susceptibility to AD. Therefore, a therapeutic approach that could circumvent the deficiencies in the cytosolic metabolism of glucose by providing glucose metabolizing intermediates, e.g., pyruvate, may hold benefits for ApoE4 carriers, who are at high risk for AD. The bioenergetic robustness may translate into enhanced synaptic activity and, ultimately, reduces the risk of developing AD and/or delays the onset of clinical manifestation.

Energy metabolism seem to play an important role in many if not all Alheimer's patients. So a ketonic diet will be a good fix, but is not an easy diet to follow and some diabetic especially have trouble achieving ketosis. Using exogenous ketones seem to work some, but I am sure is not the same.

There have been also a few studies using insulin and diabetic drugs with some success.

Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer’s disease therapeutics

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743662/

Abstract

Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol. 2011 Sep 12. Alzheimer’s disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimer’s, subsequent neurodegeneration might be prevented. Administering systemic insulin to elderly non-diabetics poses unacceptable risks of inadvertant hypoglycemia. However, intranasal delivery directs the insulin into the brain, avoiding systemic side-effects. This pilot study demonstrates both efficacy and safety of using intranasal insulin to treat early Alzheimer’s and mild cognitive impairment, i.e. the precursor to Alzheimer’s. Significant improvements in learning, memory, and cognition occured within a few months, but without intranasal insulin, brain function continued to deteriorate in measurable degrees. Intranasal insulin therapy holds promise for halting progression of Alzheimer’s disease.

Glimepiride protects neurons against amyloid-β-induced synapse damage

https://www.sciencedirect.com/science/article/pii/S0028390815301222
Abstract

Alzheimer's disease is associated with the accumulation within the brain of amyloid-β (Aβ) peptides that damage synapses and affect memory acquisition. This process can be modelled by observing the effects of Aβ on synapses in cultured neurons. The addition of picomolar concentrations of soluble Aβ derived from brain extracts triggered the loss of synaptic proteins including synaptophysin, synapsin-1 and cysteine string protein from cultured neurons. Glimepiride, a sulphonylurea used for the treatment of diabetes, protected neurons against synapse damage induced by Aβ. The protective effects of glimepiride were multi-faceted. Glimepiride treatment was associated with altered synaptic membranes including the loss of specific glycosylphosphatidylinositol (GPI)-anchored proteins including the cellular prion protein (PrPC) that acts as a receptor for Aβ42, increased synaptic gangliosides and altered cell signalling. More specifically, glimepiride reduced the Aβ-induced increase in cholesterol and the Aβ-induced activation of cytoplasmic phospholipase A2 (cPLA2) in synapses that occurred within cholesterol-dense membrane rafts. Aβ42 binding to glimepiride-treated neurons was not targeted to membrane rafts and less Aβ42 accumulated within synapses. These studies indicate that glimepiride modified the membrane micro-environments in which Aβ-induced signalling leads to synapse damage. In addition, soluble PrPC, released from neurons by glimepiride, neutralised Aβ-induced synapse damage. Such observations raise the possibility that glimepiride may reduce synapse damage and hence delay the progression of cognitive decline in Alzheimer's disease.

Diabetes drug shows promise for safely treating, detecting Alzheimer's disease

https://www.eurekalert.org/pub_releases/2017-03/bumc-dds030817.php

"A single injection of pramlintide into our patients was well tolerated and reduced the amyloid burden as well as lowered the concentrations of amyloid-β peptides, a major component of AD in the brain," explained corresponding author Wendy Qiu, MD, PhD, associate professor of psychiatry and pharmacology and experimental therapeutics at Boston University School of Medicine.

Anecdotally and I think there have been studies, coconut oil and MCT oil have been used with some success in Alzheimers, both ways to increase ketones.

You'd almost think brains aren't intended to run purely on glucose, like the idiot on a recent BBC radio programme claimed.

ps/ nor is the rest of the body