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

Albeit we know much about the pathogenesis of prion disorders, our understanding of the molecular and cellular mechanisms that govern the onset of the disease and the physiologic role of the cellular prion protein (PrPC) is still poor. Use of animal and cell models, however, has underscored a number of putative functions for the protein, 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. An intriguing hypothesis, based on increasing amounts of data that may explain the multifaceted behavior of PrPC, entails that the protein is involved in the regulation of Ca2+ homeostasis. In this respect, we have demonstrated that PrPC influences local Ca2+ movements in neurons. This was achieved by using lentiviral constructs expressing different aequorin Ca2+ probes, and primary cerebellar granule neurons (CGN) derived from WT and PrP-KO congenic mice. Recently, a few reports have shown that PrPC acts as a high-affinity receptor for the amyloid-beta (Abeta) peptide, a fragment of the amyloid precursor protein implicated in Alzheimer’s disease (AD), and that PrPC-Abeta 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 CGN – expressing or not PrPC – with oligomeric Abeta (1–42) peptides, or the shorter (1–40) fragment, deranges Ca2+ metabolism in a PrPC-dependent manner. Specifically, we have analysed Ca2+ entry through either store-operated channels, or those activated by glutamate. Here, we present preliminary results of this investigation, which suggest that Abeta could exert PrPC-dependent effects on Ca2+ metabolism of CGN.