Researchers discover how diabetes affects specific brain area leading to memory loss

Badly controlled diabetes are known to affect the brain causing memory and learning problems and even an increased incidence of dementia, although how this occurs is not clear. But now a study, by researchers from the Centre for Neuroscience and Cell Biology of the University of Coimbra in Portugal, in mice with type 2 diabetes has discovered how diabetes affects a brain area called hippocampus causing memory loss, and also how caffeine can prevents it. Curiously, the neurodegeneration that the researcher Rodrigo Cunha and his team see caused by diabetes, is the same that occurs at the first stages of several neurodegenerative diseases, including Alzheimer's and Parkinson's, suggesting that caffeine (or drugs with similar mechanism) could help them too.

Type 2 diabetes (which accounts for about 90% of all diabetic cases) is a full blown public health disaster - 285 million people already affected worldwide (6.4% of the world population) with numbers expected to almost double by 2030. And this without counting pre-diabetic individuals. The problem is that the disease is triggered by obesity, a sedentary lifestyle and bad eating habits (although there is also a genetic predisposition), all of which are increasingly widespread. All forms of diabetes are caused by high levels of sugar in the blood, but in type 2 this occurs because the body becomes increasingly resistant to insulin - the hormone that allows the cells to take the sugar from the blood to be use it as "fuel" - leading to toxic high levels of sugar in the blood that damage nerves and blood vessels and, with time, cause severe complications

In the study out now in the journal PLoS , João Duarte, Rodrigo Cunha and colleagues take advantage of a new mouse model of diabetes type 2, which like humans develops the disease in adults as result of a high-fat diet, to look at one of the least understood complications of diabetes - the disease effect on the brain, more specifically, on memory. They also looked at a possible protective effect by caffeine as this psychostimulant has been suggested to prevent memory loss in various neurodegenerative diseases, from Alzheimer's to old age dementia, and maybe even diabetes. And when we consider that coffee is the world leading beverage right after water, with about 500 billion cups consumed annually, this, if true, needs to be better understood.

For that the Portuguese researchers compared four groups of mice - diabetic or normal animals without or with caffeine (equivalent to 8 cups of coffee a day) in their water - to find that long-term consumption of caffeine not only diminished the weight gain and the high levels of blood sugar typical of diabetes, but also prevented memory loss (diabetic animals had significantly poorer memory than normal ones, while those treated with caffeine showed no problems). This confirmed that caffeine could, in fact, protect against diabetes as well as prevent memory impairment, probably by interfering with the neurodegeneration caused by toxic sugar levels.

To investigate this, next the researchers looked at a brain region linked to memory and learning, which is often atrophied in diabetics, called hippocampus. And in fact, diabetic mice showed abnormalities in this area having synaptic degeneration (synapses are the structures at the end of each neuron used to communicate between neurons) and astrogliosis. Astrogliosis is an abnormal increase of the cells that surround neurons normally as result of the death of nearby neurons. Both phenomena are known to affect memory and, again, caffeine consumption prevented the problems.

But to be able to develop drugs based on caffeine's protective effect, it was necessary to understand its molecular mechanisms. So next the researchers looked at the only brain molecules known to respond to caffeine - the adenosine receptors A1R and A2AR - in the hippocampus. And here, A2AR seemed to be the key for caffeine's memory rescue since its density - which increases with noxious insults - was high in diabetic animals but normal in those treated with caffeine. This agrees with the previous studies that shown that A2AR inhibition could protect against synaptic degeneration and memory dysfunction.

In conclusion, Duarte and Cunha's work - using an animal model of diabetes type 2 that closely mimics the human for of the disease - suggests that diabetes affects memory by causing synaptic degeneration, astrogliosis and increased levels of A2AR. These new results indicate as well that chronic consumption of caffeine can prevent the neurodegeneration and the memory impairment. And not only in diabetes, since synaptic degeneration and astrogliosis are both part of a cascade of events common to several neurodegenerative diseases what suggests that caffeine (or drugs with similar mechanisms) could help with them too.

So does this means that we should drink eight cups of coffee a day to prevent memory loss in old age or in diabetes? Not really as Rodrigo Cunha, the team leader explains: "Indeed, the dose of caffeine shown to be effective is just too excessive. All we can take from here is that a moderate consumption of caffeine should afford a moderate benefit, but still a benefit. But we need to do more research. Such experimental design is common in pre-clinical studies: in order to highlight a clear benefit, one dramatises the tested doses. Also, our ultimate goal is the design of a drug more potent and selective (i.e. with less potential side effects) than caffeine itself; animal studies enable us to pinpoint the likely target of caffeine with protective benefits in type 2 diabetes. So we will be testing chemical derivates of caffeine, which act as selective adenosine A2A receptor antagonists, to try to prevent diabetic encephalopathy. It might turn out to be a therapeutic breakthrough for this devastating disease". And with a disease that is already affecting 6.4% of the population and growing, a breakthrough can never come too soon.


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