Glucose deprivation in the brain may trigger the onset of cognitive decline, especially memory impairment – the earliest signs of Alzheimer's disease, say scientists who have also found a protein that may be targeted to treat the disorder.

The hippocampus plays a key role in processing and storing memories. However, it relies exclusively on glucose for fuel without glucose, neurons starve and eventually die.

The new study 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," said Domenico Pratico, Professor at Temple University in the US.

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.

To investigate the impact of glucose deprivation on the brain, Pratico's team used a mouse model that recapitulates memory impairments and tau pathology in Alzheimer's disease.

At about four or five months of age, some of the animals were treated with 2-deoxyglucose (DG), a compound that stops glucose from entering and being utilised 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, 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, Pratico turned to p38, which has been identified as a driver of tau phosphorylation.

In the new study, they found that memory impairment was directly associated with increased p38 activation.

"There is now a lot of evidence to suggest that p38 is involved in the development of Alzheimer's disease," Pratico said.

The findings also show 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 said.