Glucose and Alzheimer’s

laboratory miceOne of the earliest signs of Alzheimer’s is a decline in glucose levels in the brain.  Yet whether or not it’s a cause or consequence of neurological dysfunction has been debated.  However, new research at the Lewis Katz School of Medicine at Temple University unequivocally reveals that a lack of glucose triggers cognitive decline, rather than being caused by cognitive decline.  

In recent years, advances in imaging techniques, particularly positron emission tomography (PET), have allowed researchers to look for subtle changes in the brains of patients with different degrees of cognitive impairment.  A decrease in glucose availability in the hippocampus has been consistently reported.  The hippocampus plays a key role in processing and storing memories, and relies exclusively on glucose for fuel.  This new study is the first to directly link memory impairment to glucose deprivation in the brain specifically through a mechanism involving the accumulation of the protein phosphorylated tau.  Phosphorylated tau precipitates and aggregates in the brain, forming tangles inducing neuronal death.  A greater abundance of neurofibrillary tau tangles is generally associated with more severe dementia.  This is also the first to identify the protein p38 as a potential alternate drug target in treating Alzheimer’s, since they’re activated in response to glucose deprivation.  Yet these also increase tau phosphorylation in the long run, making them worse.  

To investigate the impact of glucose deprivation on the brain, the research team used a mouse model that recapitulates memory impairments and tau pathology in Alzheimer’s.  At around 4-5 months of age, some of the animals were treated with 2-DG, a compound that stops glucose from entering and buing used by cells.  After the compound was administered over time, the mice were evaluated for cognitive function.  In a series of memory-based maze tests, glucose-deprived mice performed much worse than their untreated counterparts.  

Under the microscope, neurons in the brains of DG-treated mice exhibited abnormal synaptic function, suggesting that neural communication pathways had broken down.  There was a significant reduction in long-term potentiation, the mechanism that strengthens synaptic connections to ensure memory formation and storage.  The researchers found high levels of phosphorylated tau and much higher amounts of cell death in the brains of glucose-deprived mice.  The team looked at p38, and found that it was directly associated with memory impairment.  

These findings lend support to the idea that chronically occurring, small episodes of glucose deprivation are damaging for the brain.  These types of episodes are most likely related to diabetes, where glucose can’t enter the cell.  The next step, according to researchers, is to see if memory impairments can be alleviated, despite glucose deprivation.  

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