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Alzheimer's disease (AD) is the most prevalent form of dementia and soluble amyloid β (Aβ) oligomers are thought to play a critical role in AD pathogenesis. Cellular prion protein (PrP C ) is a high-affinity receptor for Aβ oligomers and mediates some of their toxic effects. The N -terminal region of PrP C can interact with Aβ, particularly the region encompassing residues 95-110. In this study, we identified a soluble and unstructured prion-derived peptide (PrP 107-120 ) that is external to this region of the sequence and was found to successfully reduce the mitochondrial impairment, intracellular ROS generation and cytosolic Ca 2+ uptake induced by oligomeric Aβ 42 ADDLs in neuroblastoma SH-SY5Y cells. PrP 107-120 was also found to rescue SH-SY5Y cells from Aβ 42 ADDL internalization. The peptide did not change the structure and aggregation pathway of Aβ 42 ADDLs, did not show co-localization with Aβ 42 ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrP C . As a sequence region that is not involved in Aβ binding but in PrP self-recognition, the peptide was suggested to protect against the toxicity of Aβ 42 oligomers by interfering with cellular PrP C and/or activating a signaling that protected the cells. These results strongly suggest that PrP 107-120 has therapeutic potential for AD.

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative disorders showing mislocalization and cytosolic accumulation of TDP-43 inclusions in the central nervous system. The decrease in the efficiency of the clearance systems in aging, as well as the presence of genetic mutations of proteins associated with cellular proteostasis in the familial forms of TDP-43 proteinopathies, suggest that a failure of these protein degradation systems is a key factor in the aetiology of TDP-43 associated disorders. Here we show that the internalization of human pre-formed TDP-43 aggregates in the murine neuroblastoma N2a cells promptly resulted in their ubiquitination and hyperphosphorylation by endogenous machineries, mimicking the post-translational modifications observed in patients. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. The inhibition of TDP-43 proteostasis in the presence of selective inhibitors against the proteasome and macroautophagy systems revealed that these two systems are both severely involved in TDP-43 accumulation and have a strong influence on each other in neurodegenerative disorders associated with TDP-43.