Mitochondrial calcium transport remodelling (the body’s attempt to compensate for flagging energy production and metabolic dysfunction) fuels the decline in mitochondrial function, memory, and learning in Alzheimer’s patients, according to new research published in the journal Nature Communications.
“Amyloid-beta deposition and tau pathology are considered the major contributors to Alzheimer’s disease and, as a result, they have been the main focus of therapeutic development. Large clinical trials targeting these pathways have universally failed, however,” said John Elrod, the study’s senior investigator.
Calcium transport into mitochondria plays an important part in many cellular functions and requires the involvement of multiple proteins to be carried out effectively. Among the key regulators of this process is a protein known as NCLX, mediates calcium efflux from heart cells.
In their new study, Dr. Elrod and colleagues examined the role of mitochondrial calcium uptake by neurons in Alzheimer’s disease. To do so, the team used a mouse model of familial Alzheimer’s disease in which animals harboured three gene mutations that give rise to age-progressive pathology comparable to Alzheimer’s progression in human patients.
As mice carrying the three mutations aged, the researchers observed a steady reduction in NCLX expression. This reduction was accompanied by decreases in the expression of proteins that limit mitochondrial calcium uptake, resulting in damaging calcium overload. NCLX loss was further linked to increases in the production of cell-damaging oxidants.
To better understand the physiological relevance of NCLX loss, Dr. Elrod’s team next completely eliminated NCLX expression in the forebrain of Alzheimer’s disease mice. In tests for memory and cognitive function, the animals exhibited significant impairments. Analyses of brain tissue from these mice showed that NCLX reduction and the consequent loss of calcium efflux from mitochondria accelerated the development of amyloid beta and tau pathology. When NCLX expression was restored, levels of harmful protein aggregates declined, neuronal mitochondrial calcium homeostasis was re-established, and mice were rescued from cognitive decline.
“Our findings indicate that maladaptive remodeling of pathways to compensate for abnormalities in calcium regulation, which perhaps are meant to maintain energy production in cells, lead to neuronal dysfunction and Alzheimer’s pathology,” Dr. Elrod said. “Moreover, our data suggest that amyloid beta and tau pathology actually lie downstream of mitochondrial dysfunction in the progression of Alzheimer’s disease, which opens up a new therapeutic angle.”