The onset of Alzheimer’s disease can be difficult to study because changes caused by the disease can start many years before patients develop obvious symptoms. Researchers think that a disturbed calcium balance in neurons is present at the beginning of Alzheimer’s disease and probably contributes to early memory failures.
So-called plaques, i.e., protein deposits outside nerve cells in the brain, are characteristic of Alzheimer’s disease. These plaques are formed by a clumping of protein fragments consisting of amyloid ß (Aß), which is part of a precursor protein called amyloid-precursor protein (APP). The protein APLP2 is a homologue of APP. The effects of Aβ on Ca2+ handling in nerve cells have been extensively studied. However, it is not well understood how exactly APP and APLP2 influence Ca2+ homeostasis, i.e., the regulation of the calcium balance.
Martin Korte, Technische Universität Braunschweig and Helmholtz Centre for Infection Research, Braunschweig, Germany, and colleagues have investigated how APP and its homolog APLP2 control neuronal Ca2+ handling using APP/APLP2-deficient mice. The team found that the loss of both APP and APLP2 disrupts the calcium balance. APP and APLP2 control the calcium dynamics as well as the refilling of the internal calcium stores within the neurons. One effect of their loss is that the function and expression of SERCA-ATPase are disturbed. This protein is responsible for pumping released calcium within the cell back into the internal storage. The team also found that the expression of two calcium-channel-associated proteins (Stim1 and Stim2) is altered in the absence of APP and APLP2.
In addition, the researchers found that a naturally occurring cleavage product of APP, the secreted APP ectodomain APPs-α, is an essential regulator of the cellular calcium balance and could restore Ca2+ homeostasis and protein expression. A reduced production of APPsα in early Alzheimer’s disease, thus, could be a cause of the disturbed calcium balance.
Overall, this work demonstrates a central and important role of the APP protein family, specifically the extracellularly released fragment APPs-α of the APP protein, in calcium homeostasis. These findings highlight the therapeutic potential of this domain for Alzheimer’s disease therapy.
- APPsα rescues impaired Ca2+ homeostasis in APP- and APLP2-deficient hippocampal neurons,
Susann Ludewig, Ulrike Herrmann, Kristin Michaelsen-Preusse, Kristin Metzdorf, Jennifer Just, Charlotte Bold, Ulrike C. Müller, Martin Korte,
Proc. Natl. Acad. Sci. USA 2021, 118, e2011506118.