Metabolic disturbance in the brain exacerbates, may forewarn Alzheimer’s pathology

CHICAGO — A better understanding of the metabolic processes in the brain — specifically disturbances resulting from neurodegenerative diseases — has important implications for potential treatments. The research was presented at Neuroscience 2019, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

Dementia is prevalent and growing, expected to reach over 131 million in 2050. One novel area of research is the metabolism of glucose in the brain. Type 2 diabetes increases Alzheimer’s disease (AD) risk by about two-fold. The metabolism of glucose is important for brain functioning, including energy distribution and neural activity. A malfunction therefore has cascading effects. Researchers are now working to understand the exact underpinnings and consequences of such metabolic disturbance to more easily identify and treat the disease.

Today’s new findings show that:

• A “typical Western diet” (TWD) — high fat and high carbohydrate — fed to a mouse model that have certain types of AD-pathology leads to decreased brain insulin signaling and subsequently impaired memory. (Sami Gabbouj, University of Eastern Finland).
• An understudied genetic variant of apolipoprotein E called ApoE2 has neuroprotective properties against AD and a more robust metabolism of glucose than ApoE4, a risk factor for AD. Expressing ApoE2 in cells that also express ApoE4 reduces metabolic deficiencies and increases the brain’s resilience to developing AD. (Li(qin) Zhao, University of Kansas).
• A defect in the glucose transporter in mice that have AD pathology impaired the delivery of glucose to the brain, leaving extra in the blood. Improving glucose delivery in AD patients even after the disease’s trademark “plaque” has appeared may therefore offer an effective treatment. (Steven W. Barger, University of Arkansas for Medical Sciences).
• Glucose resistance and abnormal sleep patterns are prevalent in AD mice prior to the appearance of any other disease symptoms, such as cognitive decline. These findings shed light on the complex interplay between the risk factors of AD and the timing of abnormal patterns of sleep and glucose metabolism relative to AD symptoms. (Shannon L. Macauley, Wake Forest School of Medicine).

“Not much is known about the connection between dementia and the metabolic system that fuels the brain,” said press conference moderator David Holtzman, MD, a professor at Washington University and scientific director of the Hope Center for Neurological Disorders. “Further research can help us understand how to manipulate these functions for treatment purposes, as well as better identify the underpinnings of the disease.”

This research was supported by national funding agencies including the National Institutes of Health and private funding organizations. Find out more about Alzheimer’s Disease and other cognitive disorders on BrainFacts.org.

Related Neuroscience 2019 Presentation

Poster Session: Alzheimer’s Disease: Energy Homeostasis

Wednesday, Oct. 23, 8:00 a.m. – 12:00 p.m., Hall A

Metabolism-AD Press Conference Summary

• These studies provide a deeper understanding between the brain’s metabolic functions and the disruption caused by AD. It’s still not entirely clear whether these disruptions are merely a symptom of or an important causal factor in AD, but the identification of their role can potentially help with better diagnosis of the disease and/or mitigation of its effects.

High-fat diet Leads to Memory Impairment and Decreased Insulin-Akt-GSK3β Signaling in the Brain of Transgenic Mouse Model of Alzheimer’s Disease

Sami Gabbouj,

[email protected]

, Abstract 189.01

• A known link between AD and Type 2 diabetes is impaired insulin signaling, which affects molecular pathways implicated in the development of AD.
• Researchers investigated the impact of a typical Western diet on the insulin pathway in four different mouse models that develop AD pathology. Mice exposed to this diet showed decreased brain insulin signaling, which in turn resulted in impaired memory and learning.

ApoE2-Mediated Neuroprotective Mechanism Through Regulation of Glycolysis

Li(qin) Zhao,

[email protected]

, Abstract 651.06

• One genetic variant of apolipoprotein E (ApoE), ApoE2, is a neuroprotective genotype against AD. Researchers have begun to study the function of the gene and its variants.
• They found that the ApoE2 variant led to the most robust metabolism of glucose compared to ApoE4. Using a mouse model, they showed that hexokinase, a “gateway enzyme” that catalyzes the breakdown of glucose, is significantly upregulated by ApoE2 and downregulated in the presence of ApoE4. Introducing ApoE2 into ApoE4 expressing cells reduced these metabolic deficiencies.
• This glycolytic metabolism supports cellular functions and energy metabolism in the brain, impacting overall neural health. The data suggests that these features underlie one mechanism that may explain the neuroprotective role of ApoE2.

Alzheimer-related Pathology Impairs Peripheral Glucose Tolerance by Disrupting Glucose Transporter 1 Localization and Cerebral Glucose Delivery

Steven W. Barger,

[email protected]

, Abstract 651.09

• Researchers used a mouse model that develops AD pathology to identify a defect in the glucose transporter 1 (GLUT1) system, the same defect found in post-mortem human AD brains. It is believed that a consequence of amyloid beta plaque buildup in the brain is impaired glucose delivery to neurons in the brain.
• The data show that a flaw in glucose delivery to neurons leaves extra glucose in the blood, mimicking diabetes. Researchers believe that bolstering glucose delivery may be an effective treatment after amyloid beta has appeared in the brain. It is possible that this is a mechanism that contributes to why AD patients have elevated blood glucose levels, i.e., likely not from an endocrine disruption but as a result of a side effect of AD.

Aging and Pathology Cause Sleep Disruptions and Altered Metabolism in Mouse Models of Alzheimer’s Disease

Shannon L. Macauley,

[email protected]

, Abstract 651.23

• Sleep and metabolic disturbances are connected to AD. The response in mice that develop AD pathology to induced hyper- and hypoglycemia was abnormal before the appearance of other clinical symptoms, like cognitive decline and amyloid beta plaques. The glycemic changes impacted sleeping patterns as a result. Thus, AD pathology affects both metabolism and sleep function.
• Researchers are working to understand the interplay between and the timing of risk factors in relation to the disease for better diagnosis and treatment.

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About the Society for Neuroscienc

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The Society for Neuroscience is the world’s largest organization of scientists and physicians devoted to understanding the brain and nervous system. The nonprofit organization, founded in 1969, now has nearly 37,000 members in more than 90 countries and over 130 chapters worldwide.