Glucose Deprivation in Alzheimer's Disease Progression

The progression of Alzheimer's disease, happening in the midst of aging in general, and often other unrelated neurodegeneration as well, is so complex and sweeping that every research group focuses down on just one part of the whole. It is like the parable of the elephant and the blind men, and has made it perhaps more challenging than it might otherwise be to understand and target root causes rather than intermediary, downstream processes in the pathology of the condition. You might look at yesterday's thoughts on Alzheimer's as a consequence of lack of oxygen in brain tissues and compare with this view of Alzheimer's as a lack of glucose, for example. These are just small pieces of a bigger picture, in a field in which there needs to be a lot more synthesis of disparate research into a uniform whole.

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 now shows unequivocally 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 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. In general, a greater abundance of 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, researchers 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, researchers 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 also lend support to the idea that chronically occurring, small episodes of glucose deprivation are damaging for the brain. The next step is to inhibit p38 to see if memory impairments can be alleviated, despite glucose deprivation.

Link: http://www.templehealth.org/News/Default.aspx?nid=3626

Comments

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.