Glucose deprivation in the brain sets stage for Alzheimer's disease, study shows

January 31, 2017, Temple University
Domenico Praticò, MD, Professor in the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University Credit: Lewis Katz School of Medicine at Temple University

One of the earliest signs of Alzheimer's disease is a decline in glucose levels in the brain. It appears in the early stages of mild cognitive impairment—before symptoms of memory problems begin to surface. Whether it is a cause or consequence of neurological dysfunction has been unclear, but new research at the Lewis Katz School of Medicine at Temple University now shows unequivocally that glucose deprivation in the brain triggers the onset of cognitive decline, memory impairment in particular.

"In recent years, advances in imaging techniques, especially (PET), have allowed researchers to look for subtle changes in the brains of patients with different degrees of cognitive impairment," explained Domenico Praticò, MD, Professor in the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University (LKSOM). "One of the changes that has been consistently reported is a decrease in glucose availability in the hippocampus."

The hippocampus plays a key role in processing and storing memories. It and other regions of the brain, however, rely exclusively on glucose for fuel—without glucose, neurons starve and eventually die.

The new study, published online January 31 in the journal Translational Psychiatry, is the first to directly link memory impairment to glucose deprivation in the brain specifically through a mechanism involving the accumulation of a protein known as phosphorylated tau.

"Phosphorylated tau precipitates and aggregates in the brain, forming tangles and inducing neuronal death," Dr. Praticò explained. In general, a greater abundance of neurofibrillary tau tangles is associated with more severe dementia.

The study also is the first to identify a protein known as p38 as a potential alternate drug target in the treatment of Alzheimer's disease. Neurons activate p38 protein in response to glucose deprivation, possibly as a defensive mechanism. In the long run, however, its activation increases tau phosphorylation, making the problem worse.

brain
Credit: public domain

To investigate the impact of glucose deprivation on the brain, Dr. Praticò's team used a mouse model that recapitulates memory impairments and tau pathology in Alzheimer's disease. At about 4 or 5 months of age, some of the animals were treated with 2-deoxyglucose (DG), a compound that stops glucose from entering and being utilized by cells. The compound was administered to the mice in a chronic manner, over a period of several months. The animals were then evaluated for cognitive function. In a series of maze tests to assess memory, glucose-deprived mice performed significantly worse than their untreated counterparts.

When examined microscopically, neurons in the brains of DG-treated mice exhibited abnormal synaptic function, suggesting that neural communication pathways had broken down. Of particular consequence was a significant reduction in long-term potentiation- - the mechanism that strengthens synaptic connections to ensure memory formation and storage.

Upon further examination, the researchers discovered high levels of and dramatically increased amounts of cell death in the brains of glucose-deprived mice. To find out why, Dr. Praticò turned to p38, which in earlier work his team had identified as a driver of tau phosphorylation. In the new study, they found that memory impairment was directly associated with increased p38 activation.

"The findings are very exciting," Dr. Praticò said. "There is now a lot of evidence to suggest that p38 is involved in the development of Alzheimer's disease."

The findings also lend support to the idea that chronically occurring, small episodes of glucose deprivation are damaging for the brain. "There is a high likelihood that those types of episodes are related to diabetes, which is a condition in which glucose cannot enter the cell," he explained. "Insulin resistance in type 2 diabetes is a known risk factor for dementia."

According to Dr. Praticò, the next step is to inhibit p38 to see if can be alleviated, despite glucose deprivation. "It is an exciting avenue of research. A drug targeting this protein could bring big benefits for patients," he added.

Explore further: Mouse model points to potential new treatment for Alzheimer's disease

Related Stories

Mouse model points to potential new treatment for Alzheimer's disease

January 5, 2017
Treatment with an inhibitor of 12/15-lipoxygenase, an enzyme elevated in patients with Alzheimer's disease (AD), reverses cognitive decline and neuropathology in an AD mouse model, reports a new study in Biological Psychiatry. ...

Chronic sleep disturbance could trigger onset of Alzheimer's

March 18, 2014
People who experience chronic sleep disturbance—either through their work, insomnia or other reasons—could face an earlier onset of dementia and Alzheimer's, according to a new pre-clinical study by researchers at Temple ...

New research points to potential treatment for memory loss activating a protein dysregulated in dementia

January 31, 2017
A new study, published on the cover of the scientific journal Biological Psychiatry and lead by Dr Carlos Saura from the Institut de Neurociències (INc) at the Universitat Autònoma de Barcelona (UAB), reveals a new molecular ...

Stress hormone could trigger mechanism for the onset of Alzheimer's

June 21, 2013
(Medical Xpress)—A chemical hormone released in the body as a reaction to stress could be a key trigger of the mechanism for the late onset of Alzheimer's disease, according to a study by researchers at Temple University.

Brain cells mobilize sugar in response to increased activity

January 24, 2017
New research is providing insights into why the brain is so reliant on sugar to function.

Protein in the brain could be a key target in controlling Alzheimer's

January 25, 2012
A protein recently discovered in the brain could play a key role in regulating the creation of amyloid beta, the major component of plaques implicated in the development of Alzheimer's disease, according to researchers at ...

Recommended for you

Scientists discover why some people with brain markers of Alzheimer's have no dementia

August 16, 2018
A new study from The University of Texas Medical Branch at Galveston has uncovered why some people that have brain markers of Alzheimer's never develop the classic dementia that others do. The study is now available in the ...

Researchers identify new genes that may contribute to Alzheimer's disease

August 14, 2018
Researchers from Boston University School of Medicine, working with scientists across the nation on the Alzheimer's Disease Sequencing Project (ADSP), have discovered new genes that will further current understanding of the ...

Deaths from resident-to-resident incidents in dementia offers insights to inform policy

August 14, 2018
Analyzing the incidents between residents in dementia in long-term care homes may hold the key to reducing future fatalities among this vulnerable population, according to new research from the University of Minnesota School ...

Scientists propose a new lead for Alzheimer's research

August 14, 2018
A University of Adelaide-led team of scientists has suggested a potential link between iron in our cells and the rare gene mutations that cause Alzheimer's disease, which could provide new avenues for future research.

Eye conditions provide new lens screening for Alzheimer's disease

August 8, 2018
Alzheimer's disease is difficult to diagnose as well as treat, but researchers now have a promising new screening tool using the window to the brain: the eye.

Potential indicator for the early detection of dementias

August 7, 2018
Researchers at the University of Basel have discovered a factor that could support the early detection of neurodegenerative diseases such as Alzheimer's or Parkinson's. This cytokine is induced by cellular stress reactions ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.