Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease

Article type: Review Article

Authors: Crestini, Alessio^a | Santilli, Francesca^{b; c} | Martellucci, Stefano^b | Carbone, Elena^a | Sorice, Maurizio^c | Piscopo, Paola^a | Mattei, Vincenzo^{b; c; *}

Affiliations: [a] Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy | [b] Biomedicine and Advanced Technologies Rieti Center, “Sabina Universitas”, Rieti, Italy | [c] Department of Experimental Medicine, “Sapienza” University, Rome, Italy

Correspondence: [*] Correspondence to: Vincenzo Mattei, Biomedicine and Advanced Technologies Rieti Center, “Sabina Universitas”, Via Angelo Maria Ricci, 35/A – 02100, Rieti, Italy. Tel.: +39 07461739607; E-mail: v.mattei@sabinauniversitas.it.

Abstract: Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

Keywords: Alzheimer’s disease, Aβ oligomers, amyloid-β , amyloid-β protein precursor, neurodegenerative diseases, prion protein, prion protein refolding, prions, tau pathologies AβO-induced signal cascade

DOI: 10.3233/JAD-215171

Journal: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 503-518, 2022