Source: SfN.
Researchers say promoting conversion of glucose into brain energy could reduce risk factors and delay disease onset for those who carry Alzheimer’s associated genes.
The strongest genetic risk factor for Alzheimer’s disease may impair the brain’s ability to convert its primary fuel source into usable energy, finds a study of female mice published in JNeurosci. The research suggests therapeutic strategies that promote brain energy conversion in risk gene carriers could help to reduce risk or delay onset of the disease.
Approximately 20 percent of people produce a version of human apolipoprotein E called ApoE4, which increases their risk of developing Alzheimer’s disease, while the five percent of people who produce the rare ApoE2 appear to show some protection against Alzheimer’s.
Liqin Zhao and colleagues explored the influence of these ApoE variations — in addition to the most common ApoE3 that does not confer risk for or protection against Alzheimer’s disease — on the chemical reactions that transform glucose and ketone bodies into the form of energy used by cells. The brains expressing the three types of proteins handled the process differently, which may underlie their distinct effects on Alzheimer’s risk and protection. While the ApoE4 brains struggled to use glucose, they appeared to utilize ketone bodies — the brain’s secondary fuel source — to compensate for the energy deficiency.
About this neuroscience research article
Funding: NIH/National Institute on Aging, NIH/National Institute of General Medical Sciences, University of Kansas funded this study.
Source: David Barnstone – SfN
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer’s Disease Risk Reduction and Early Intervention” by Long Wu, Xin Zhang and Liqin Zhao in Journal of Neurosciene. Published July 2 2028.
Abstract
Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer’s Disease Risk Reduction and Early Intervention
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.
https://neurosciencenews.com/genetics-alzheimers-9499/
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