Investigating the role of the cellular prion protein in Alzheimer's disease

The mechanism of prion related neurodegeneration and the physiologic role of cellular prion protein (PrPC) are still ill-defined. Use of animal and cell models has underscored a number of putative functions, suggesting that PrPC serves in cell adhesion, migration, proliferation and differentiation, possibly by interacting with extracellular partners, or by taking part in multi-component signaling complexes at the cell surface. In this respect, we have demonstrated that PrPC influences local Ca2+ movements in neurons. Recently, some reports have also shown that PrPC acts as a high-affinity receptor for the amyloid-b (Ab) peptide, a fragment of the amyloid precursor protein implicated in Alzheimer’s disease (AD), and that PrP-Ab interactions may be fundamental for AD-related impairment of synaptic plasticity. Given that synaptic plasticity is closely related to Ca2+ homeostasis, we have adopted the aequorin strategy to investigate whether treatment of primary cerebellar granule neurons (CGN)–expressing or not PrPC–with monomeric or oligomeric Ab (1-40) and (1-42) peptides, deranges Ca2+ metabolism in a PrP-dependent manner. Specifically, we have analysed Ca2+ variations in plasma membrane domains following Ca2+ entry through both store-operated channels and NMDA and other glutamate receptors.