Mitochondrial Ca2+ uptake in the pathogenesis of familial Alzheimer’s disease

Alzheimer's disease is a slowly progressive degenerative dementia primarily characterized by the death of nervous cells, with consequent mood swings, gradual loss of memory and language, that eventually leads to the failure of self-care abilities and premature death. Generally, Alzheimer's disease is sporadic, with no apparent underlying causes, but in 1 out of 10 cases the disease is determined by well-defined genetic defects. The mechanisms that trigger the loss of nervous cells are still largely unknown, despite several hypotheses have been proposed. This research proposal wants to explore one of these mechanisms, the contribution of mitochondrial Ca2+ accumulation to neuronal cell death. Mitochondria are small specialized subunits present in every cell type. Their primary function is to produce energy for the whole cell in the form of a small molecule called ATP, that represent the common fuel for all cellular reactions. The accumulation of Ca2+ cations inside mitochondria is a signal necessary to sustain energy production. However, too much Ca2+ inside mitochondria (a phenomenon known as “mitochondrial Ca2+ overload”) can also lead to cell death. Nervous cells normally require a lot of energy to preserve their functions and are thus considered to be particularly sensitive to mitochondrial Ca2+ overload. However, this possibility has never been directly tested, because the molecular identity of mitochondrial Ca2+ channels was unknown until few years ago when the principal investigator of this project finally identified the mechanism of mitochondrial Ca2+ accumulation. This project will test whether the prevention of mitochondrial Ca2+ overload can efficiently protect mouse model of inherited Alzheimer's disease from the death of nervous cells. If the hypothesis is correct, it is expected that a cellular component will be identified that represents a novel target for the development of innovative drugs for the treatment of Alzheimer's disease.