The cellular prion protein (PrPC) is a protein mostly expressed at the plasma membrane of neurons. Its transconformation into the pathogenic prion PrPSc is at the root of prion diseases. It is clearly established that the PrPSc-induced neurodegeneration depends on the expression of PrPC in neurons and results from the corruption of PrPC function(s) by PrPSc. Unravelling the role of PrPC is thus a prerequisite to grasp neurodegeneration mechanisms in prion diseases. Part of my work shows that PrPC exerts a cytoprotective function against TNFalpha inflammatory cytokine. PrPC silencing in neurons (PrPnull-neurons) renders these cells highly sensitive to TNFalpha due to surface accumulation of TNFalpha receptor (TNFR). My work demonstrates that the loss of PrPC regulatory function on the clustering and signaling downstream of bêta 1 integrins in PrPnull neurons provokes the overactivation of the kinase PDK1, subsequent internalization of TACE alpha-secretase, and uncoupling of TACE from TNFR substrate. Because of the phenotypic proximity between PrPnull neurons (Ezpeleta et al. 2017) and PrPSc-infected neurons (Pietri et al. 2013; Alleaume-Butaux et al. 2015), my work supports the view of a loss of PrPC protective function in prion diseases. As concerns prion infection, my work shows that after PDK1 overactivation, internalized TACE is uncoupled from another substrate, the amyloid peptides precursor protein (APP), leading to the accumulation of neurotoxic peptides Abêta 40 and Abêta 42, hallmarks of Alzheimer's disease. Within a prion infectious context, Abêta 40/42 peptides are predominantly present as monomers, and to a lesser extent, as trimers and tetramers. By combining in vitro and in vivo approaches, we show that Abêta peptides produced by infected neurons do not alter replication nor the infectivity of prions. Nevertheless, we demonstrate that oligomerized Abêta is able to form amyloid plaques in the brain of transgenic APP23 mice infected by prions. In these mice, Abêta deposits accelerate prion pathogenesis. The last axis of my work deals with nanoparticles, that is, nanometric materials commonly found in manufactured products and industrial processes. My work shows that, as PrPSc and Abêta, titanium dioxide or carbon black assemblies interact with PrPC at the surface of neurons and deviate its signaling function, which leads, inter alia, to PDK1 overactivation, TACE internalization, TNFR accumulation at the plasma membrane, and neuronal cells hypersensitivity to TNFalpha inflammatory stress. We also found that nanoparticle-induced TACE uncoupling from APP increases Abêta peptide production by neurons. Even if no epidemiological study has demonstrated to date a link between nanoparticle exposure and Alzheimer's disease, my work suggests an causal implication of nanoparticles in the initiation or amplification of this disease.