On 29 August, Dr Pooja Jadiya and colleagues published a paper in Nature Communications, showing that cognitive decline in animal models of AD is linked to calcium overload in dysfunctional mitochondria within brain cells.
Mitochondria are often described as the powerhouses of cells, responsible for generating energy-rich molecules by breaking down sugars, lipids and other compounds within the cell. A single cell can contain up to 2000 mitochondria, with the number of mitochondria varying according to the size, function and energetic requirements of the cell. In addition to their energy-generating function, mitochondria also play an important role in the regulation of calcium transport in and out of the cell. This, in turn, impacts the ability of mitochondria to fulfil their other functions. For example, when mitochondria are overloaded with calcium they aren’t able to properly generate energy, leading to the production of damaging free radicals. Interestingly, previous studies have shown that calcium accumulates inside neurons during the development of AD. Researchers have theorised that this calcium overload may promote the formation of amyloid plaques – and that amyloid, in turn, may cause further calcium disturbances, creating a vicious cycle of calcium dysregulation and amyloid accumulation that ultimately leads to neurodegeneration and memory loss.
In their new study, Dr Jadiya and colleagues set out to examine the role of mitochondrial calcium uptake in the development of AD, using animal models of disease to genetically dissect the function of specific calcium-regulating proteins. To check for genes that were relevant to human disease, the researchers first looked at brain samples donated by people with AD or healthy volunteers. They noticed that brain samples from people with AD had substantially lower levels of a gene called NCLX, which encodes a protein that helps transport calcium out of mitochondria. Moving into mouse models of AD, they showed that levels of NCLX gradually reduced as AD mice aged: at the same time, calcium accumulation in the mitochondria of brain cells gradually increased. When the NCLX gene was removed in AD mice, animals developed signs of cognitive impairment at a much faster rate than normal, associated with increased amyloid plaque formation. However, when NCLX was restored, mice regained cognitive function and their mitochondria were found to be normal, without the high levels of calcium accumulation observed in mice lacking NCLX.
Based on these findings, Dr Jadiya and colleagues suggest that mitochondrial calcium overload may be a starting point for AD development, with amyloid plaque formation happening partly as a result of mitochondrial dysfunction.
https://www.nature.com/articles/s41467-019-11813-6#author-information