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.”
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
- 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
- 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
- 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
- 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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