IP3R dysregulation as a proximal event in Alzheimer’s disease: exploring and exploiting Bcl-2 proteins

 Alzheimer’s disease, the most frequent form of dementia, has an enormous impact on quality of life and society. 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 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 Alzheimer’s disease onset is deranged calcium (Ca2+) signaling, exactly the aim of this project.
The consortium will focus on the role of IP3 receptors, intracellular Ca2+ channels, and their modulation by Bcl-2, a major anti-cell death protein. Bcl-2 serves as an inhibitor of IP3 receptors keeping these channels in check. Now, we wish to examine whether (i) alterations in IP3 receptor / Bcl-2-complex formation and modulation could underlie Ca2+-signaling dysregulation in Alzheimer’s disease and (ii) the properties of Bcl-2 proteins in inhibiting IP3 receptors could be exploited to prevent or at least delay Alzheimer’s disease features by supporting memory function, maintaining neuronal morphology and sustaining neuronal survival.
Thanks to the complementary expertise of its partners, the project will apply an integrated approach, from biochemical & cell biological studies at the (sub)cellular level to ex vivo work in brain samples and in vivo studies in mice.