A link between diabetes and Alzheimer's disease. Can we help brain cells adapt to stress?

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. This degenerative brain disease typically begins with a subtle decline in memory, and progresses to global deterioration in intellectual abilities, particularly memory, problem solving, judgment, awareness and behaviour. More than 14% of people over 65 have AD, increasing to at least 40% in those over 80.

Type 2 diabetes mellitus (T2DM) is a metabolic disease that affects 7% of the global population and the incidence is rising to epidemic proportions. Diabetes often results in microvascular (small blood vessel) and macrovascular (large blood vessel) disease, and leads to complications such as lesions in the retina, nerve damage, coronary heart disease and stroke. There is now significant evidence that T2DM can also cause complications within the central nervous system that may include structural alterations or wasting of the brain, as well as changes in the electrical activity of the brain that ultimately result in a reduction in mental performance.

Many studies have shown that having T2DM significantly increases the risk of developing AD. Both diseases share several common abnormalities including decreased availability of glucose, the brain's main source of energy; decreased ability to respond to the effects of insulin, a hormone that facilitates entry of glucose into some cells; increased oxidative stress leading to cell damage; and deposition of damaging proteins. There is a good deal of evidence to suggest that these two diseases disrupt common cellular and molecular pathways, and that each disease assists the progression of the other. Results from our lab at the University of Coimbra, Portugal, reinforce the view that a strong correlation exists between T2DM and AD, and that one of the components of cells - the mitochondria - are fundamental links in this process. It seems that the mitochondrial dysfunction associated with AD is exacerbated by T2DM (and prediabetic states) and vice versa.

Mitochondria - known as the "power stations" of the cell - are increasingly recognized as essential for generating the energy that fuels normal cellular function. At the same time, they monitor cellular health in order to initiate programmed cell death if this is necessary: for instance, if cells are irreversibly damaged they need to be removed to prevent propagation of damage. As such, the mitochondria sit at a strategic position in the hierarchy of cellular organelles and can continue the healthy life of the cell or terminate it. Currently, we are trying to clarify the role of mitochondria and their associated signalling pathways in the dysfunction of neurons and brain endothelial cells (cells that line the inside of blood vessels) that occur in AD and T2DM. As we have seen, mitochondria can activate pro-survival or pro-death pathways, and usually under pathological conditions the pro-death pathways prevail. It is known that in AD, the endothelial cells suffer cellular and biochemical alterations and release toxic factors that predispose neurons to degeneration and death. Despite this evidence, the contribution of neuronal and brain endothelial mitochondria to the neurodegenerative processes associated with AD and/or T2DM remains an open question. Hopefully, our studies will help to answer this.

The realization that mitochondria are at the intersection of the life and death of the cell has made them a promising target for drug discovery and therapeutic interventions. To this end, we are interested in clarifying if mitochondria or their signalling pathways can be manipulated to promote preconditioning-induced brain tolerance. This is an adaptive response that protects the brain against the same stress - that is, noxious stimuli - or against a different stress. The brain is capable of withstanding enormous stress, but even more impressive than its durability is its capacity to adapt to stress. The phenomenon of preconditioning offers a unique window into the self-generated protective mechanisms that cells use to avoid irreversible injury.

Our team at Coimbra believes that mitochondrial function can be controlled to provide protection from a host of neuropathological conditions such as AD. We are confident that our research will provide new data that could be used for the development of novel treatments to increase the protective mechanisms that brain cells already have, and that this will allow them to resist conditions that would otherwise have been lethal.