Presenilin-2 (PS2) plays a crucial role in ensuring mitochondria work as intended in a cell, and may contribute to mitochondrial dysfunction in patients with Alzheimer’s disease (AD), new research reports.
The study “Presenilin 2-Dependent Maintenance of Mitochondrial Oxidative Capacity and Morphology” was published in the journal Frontiers in Physiology.
Alzheimer’s patients show metabolic dysfunction at a very early stage in the disease, and problems with the workings of mitochondria — the powerhouse or energy-producing parts of a cell — are known to have a role in AD progression. Studies done on tissue sample show mitochondrial dysfunction to be highly prevalent in these patients.
Presenilins, including PS1 and PS2, are proteins that affect the workings of mitochondria and are also directly implicated in the development of Alzheimer’s. Presenilins are a part of a complex called γ-secretase, which is directly involved in producing the amyloid-beta plaques seen in patients with AD. However, their exact role in mitochondrial dysfunction is not known.
Researchers at Université catholique de Louvain, in Belgium, set out to determine the precise contribution of the various presenilins to mitochondria and exactly how the individual presenilins, PS1 and PS2, contribute to the process.
Researchers conducted metabolic measurements on cells from mouse embryos that either had the wild-type (normal) PS, PS1/2 double knockout, a PS1 knockout, or a PS2 knockout. Knockout indicates that the gene is no longer being expressed, meaning it is not synthesizing a functional product, like a protein. Thus, in a PS1 and PS2 knockout embryo, the respective genes are not being expressed, while in a PS1/2 double knockout, neither gene is being expressed.
Researchers demonstrated that PS2, but not PS1, is crucial to cell metabolism. Specifically, they determined that PS2 plays a role in oxidative phosphorylation, which is the primary way through which a cell gets energy in the presence of oxygen. In fact, cells from the PS2 knockout embryos have an altered capacity to conduct oxidative phosphorylation, matched by a physically altered shape to their mitochondria.
PS2 knockout cells also showed a higher capacity for glycolysis, which is a less productive way of producing cellular energy. Researchers demonstrated that all of these effects were due to PS2, as re-expression of PS2 in the PS2 knockout embryos restored a normal cell metabolism process. Therefore, PS2 plays a major role in oxidative phosphorylation and glycolysis.
“Our data clearly demonstrate here the crucial role of PS2 in mitochondrial function and cellular bioenergetics,” the researchers wrote.
With regard to Alzheimer’s, they added: “This implies that impairment of these PS2-dependent processes could be involved in the progression of pathologies like AD in which PS2 play a key role. Investigation in an oxidative model and particularly in neurons are required to further explore this hypothesis.”