Cellular prion protein in Alzheimer’s disease: Molecular insights and behavior implications
von Angela Patricia Da Silva Correia
Datum der mündl. Prüfung:2023-12-14
Erschienen:2024-01-11
Betreuer:Prof. Dr. Inga Zerr
Gutachter:Prof. Dr. Tiago Fleming Outeiro
Gutachter:PD Dr. Roberto Goya-Maldonado
Gutachter:Prof. Dr. André Fischer
Gutachter:Prof. Dr. Rubén Fernández-Busnadiego
Gutachter:Prof. Dr. Oliver Wirths
Dateien
Name:PhD_Thesis_Angela_Patricia_da_Silva_Correia_final.pdf
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Zusammenfassung
Englisch
Alzheimer’s disease (AD) poses a substantial and increasing challenge, particularly due to our aging population, and its underlaying pathophysiology remains a topic of ongoing debate. Cellular prion protein (PrPC) has surfaced as key player in Aβ induced toxicity in AD. Our research aimed to shed light on PrPC’s function in this context. I found a robust interaction between PrPC and Aβ1-40, and Aβ1-42 via surface plasmon resonance (SPR). Further exploration in PrPC overexpressing SH-SY5Y cells revealed its role as facilitator of Aβ internalization increasing the intracellular amount of oligomeric Aβ of more than 200%. In vivo studies using double transgenic 5xFADPrnp+ / + , 5xFADPrnp+ / - , and 5xFADPrnp- / - mice demonstrated a dose dependent correlation between PrPC levels and reduction of the lifespan of about 50%. A comprehensive battery of behavioral tests, encompassing cognitive and motor function assessments, revealed a significant impact of PrPC levels on the onset and severity of cognitive and motoric impairments. However, PrPC ablation did not fully restore Aβ provoked deficits and the observed deficits in behavior. The study also identified that PrPC modulates the correlation between soluble Aβ levels and behavioral impairments. In the absence of PrPC, the behavioral impairments were no longer directly linked to soluble Aβ levels, suggesting other conformations of Aβ, rather than its total levels, may play a crucial role in Aβ related toxicity. Moreover, using 3-D light sheet microscopy combined with QUINT analyses, our findings provided evidence that PrPC may influence the overall burden of plaques but the distribution of Aβ in different brain regions. Additionally, a novel interaction between Aβ oligomers, PrPC and Cav-1 was identified in cortical neurons, Cav-1 knockout cortical neurons reveled a significant reduction of intracellular Aβ oligomers in comparison with WT cortical neurons (reduction of ~ 25 to 50%), indicating Cav-1 role facilitating the internalization of Aβ-PrPC complexes in neurons. Our research highlights PrPC as promising candidate for future AD therapeutic strategies and introduces a novel mechanism perspective in AD pathogenesis.
Keywords: Alzheimer; Prion; cellular prion protein; PrPC; Aβ; Amyloid-beta
Schlagwörter: Alzheimer; PrPC; Prion; Cellular Prion Protein; Amyloid-beta; Aβ