Though scant progress has been made in treating or understanding Alzheimer's disease in the last 100 years, one thing is known; there are declines in glucose levels in the hippocampus early on. What has remained unclear is whether that is a cause or consequence. 

A new Translational Psychiatry study in mice declares that glucose deprivation in the brain triggers the onset of cognitive decline, memory impairment in particular. 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 study link memory impairment to glucose deprivation in the brain specifically through a mechanism involving the accumulation of a protein known as phosphorylated tau. The study also found that a protein known as p38 is 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.

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 phosphorylated tau 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.

That is not to say this is relevant to humans, mice are not little people. If they were, every disease would have been cured by drugs thousands of times.