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 (Aguzzi et al., 2008), possibly by interacting with extracellular partners, or by taking part in multi-component signaling complexes at the cell surface (Linden et al., 2008). 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 (Lazzari et al., 2011). Recently, a few reports have suggested that PrPC could act as a high-affinity receptor for the amyloid-β (Aβ) peptide, a fragment of the amyloid precursor protein implicated in Alzheimer’s disease (AD), and that PrPC-Aβ interactions may be fundamental for AD-related impairment of synaptic plasticity (Laurén et al., 2009; Gimbel et al., 2010, Freir et al., 2011). 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 Aβ (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, and those activated by glutamate. Here, we present preliminary results of this investigation, which suggest that Aβ could exert PrPC-dependent effects on the Ca2+ metabolism of CGN. Aguzzi A. et al. (2008) The prion's elusive reason for being. Annu. Rev. Neurosci. 31:439-477. Freir D.B. et al. (2011) Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nat. Commun. 2:336. Gimbel D.A. et al. (2010) Memory impairment in transgenic Alzheimer mice require cellular prion protein. The Journal of Neuroscience 30: 6367-6374. Laurén J. et al. (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457: 1128-1132. Lazzari C. et al. (2011) Cellular prion protein is implicated in the regulation of local Ca2+ movements in cerebellar granule neurons. Journal of Neurochemistry 116:881-90. Linden R. et al. (2008) Physiology of the prion protein. Physiol. Rev. 88: 673-728.

INVESTIGATING THE ROLE OF THE CELLULAR PRION PROTEIN IN ALZHEIMER’S DISEASE

CASTELLANI, ANGELA;PEGGION, CATERINA;BERTOLI, ALESSANDRO;SORGATO, MARIA CATIA
2012

Abstract

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 (Aguzzi et al., 2008), possibly by interacting with extracellular partners, or by taking part in multi-component signaling complexes at the cell surface (Linden et al., 2008). 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 (Lazzari et al., 2011). Recently, a few reports have suggested that PrPC could act as a high-affinity receptor for the amyloid-β (Aβ) peptide, a fragment of the amyloid precursor protein implicated in Alzheimer’s disease (AD), and that PrPC-Aβ interactions may be fundamental for AD-related impairment of synaptic plasticity (Laurén et al., 2009; Gimbel et al., 2010, Freir et al., 2011). 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 Aβ (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, and those activated by glutamate. Here, we present preliminary results of this investigation, which suggest that Aβ could exert PrPC-dependent effects on the Ca2+ metabolism of CGN. Aguzzi A. et al. (2008) The prion's elusive reason for being. Annu. Rev. Neurosci. 31:439-477. Freir D.B. et al. (2011) Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nat. Commun. 2:336. Gimbel D.A. et al. (2010) Memory impairment in transgenic Alzheimer mice require cellular prion protein. The Journal of Neuroscience 30: 6367-6374. Laurén J. et al. (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457: 1128-1132. Lazzari C. et al. (2011) Cellular prion protein is implicated in the regulation of local Ca2+ movements in cerebellar granule neurons. Journal of Neurochemistry 116:881-90. Linden R. et al. (2008) Physiology of the prion protein. Physiol. Rev. 88: 673-728.
Biology and Translational Aspects of Neurodegeneration
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2584644
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact