IP3 receptor dysregulation as a proximal event in Alzheimer's disease: exploring ans exploiting Bcl-2 proteins. (SAO IP3 receptor)

Alzheimer’s disease, the most frequent form of dementia, which has an enormous impact on quality of life and society. Mutations in presenilins are an important risk factor of developing familial Alzheimer’s disease.  At late stages, the disease is characterized by toxic protein aggregates (amyloid beta) and the demise of cells in the brain (neurons) responsible for memory function. While neuronal loss cannot be reverted and lost neurons cannot be replaced, it is possible to delay this process. Thus, it is instrumental to focus on the early stages in the Alzheimer’s disease development. One of the key features underlying the early phases of Alzheimer’s disease is deranged calcium (Ca2+) signaling. Mutant presenilins are known to modulate IP3 receptor-mediated Ca2+ release, a ubiquitously expressed Ca2+ channel at the endoplasmic reticulum.

In this project we will focus on the role of deranged IP3 receptor mediated Ca2+ release triggered by presenilin mutations and how this influences downstream processes. In addition, we will address whether Bcl-2, a major anti-cell death protein and inhibitor of IP3 receptor function, can modulate/ this normalize these aberrant IP3 receptor responses.