Alzheimer's disease (AD) is a neurodegenerative disease characterized by synaptic dysfunction, memory loss, neuroinflammation and neuronal death that afflicts over 55 million people worldwide for which the available drugs concentrate their action at the neurotransmitter level. A possible therapeutic alternative can be found in the study of the interaction of the prion protein (PrPC) with the oligomers of Tau (TauOs). This study investigates the role of PrPC in mediating TauOs-induced alterations at the synaptic and cognitive levels by defining whether or not PrPC could represent a new molecular target to prevent cognitive decline in AD. Our PrPKO experimental models demonstrate the efficacy in preventing, contrary to what happens in WT models, the cognitive deficits acutely induced by intracerebroventricularly injected TauOs. Through electrophysiological analysis we confirmed that PrPC also mediates the TauOs-induced impairment of LTP. Biochemical studies have allowed us to confirm, in agreement with what is present in the literature, a different expression of synaptic proteins after treatment with TauOs and an increase in GluR1 receptors. Ultimately we studied the involvement of glial cells in the presence and absence of PrPC, considering that the cognitive impairment induced by AβOs and α-SynOs is associated with an activation of astrocytes and microglia. Our analyses, although not significantly, showed that TauOs activate microglia, but only in the presence of PrPC. In conclusion, the data obtained clearly show that PrPC acts as a mediator of TauOs-induced damage and may therefore represent a new possible therapeutic target for the treatment of AD and other tauopathies.
Il morbo di Alzheimer (AD) è una malattia neurodegenerativa caratterizzata da disfunzione sinaptica, perdita di memoria, neuroinfiammazione e morte neuronale che affligge oltre 55 milioni di persone in tutto il mondo per la quale i farmaci a disposizione concentrano la loro azione a livello neurotrasmettitoriale. Una possibile alternativa terapeutica la si trova nello studio dell’interazione della proteina prionica (PrPC) con gli oligomeri di Tau (TauOs). Questo studio approfondisce il ruolo di PrPC nel mediare le alterazioni indotte dai TauOs a livello sinaptico e cognitivo definendo se PrPC possa o meno rappresentare un nuovo target molecolare per prevenire il declino cognitivo nell’AD. I nostri modelli sperimentali PrPKO dimostrano l’efficacia nel prevenire, contrariamente a quanto accade nei modelli WT, i deficit cognitivi indotti acutamente da TauOs iniettati intracerebroventricolarmente. Attraverso analisi di elettrofisiologia abbiamo confermato che PrPC media anche la compromissione indotta dai TauOs dell’ LTP. Gli studi di biochimica ci hanno permesso di confermare, in accordo con quanto presente in letteratura, una diversa espressione di proteine sinaptiche dopo il trattamento con TauOs e un aumento dei recettori GluR1. In ultima analisi abbiamo studiato il coinvolgimento delle cellule gliali in presenza e in assenza di PrPC, considerando che il danno cognitivo indotto da AβOs e α-SynOs si associa ad un’attivazione di astrociti e microglia. Le nostre analisi, seppure non in modo significativo, hanno mostrato che i TauOs attivano la microglia, ma solo in presenza di PrPC. In conclusione, i dati ottenuti mostrano chiaramente che PrPC funge da mediatore dei danni indotti da TauOs e può quindi rappresentare un nuovo possibile target terapeutico per la cura dell’AD e di altre tauopatie.
Oligomeri tau e proteina prionica: un'interazione pericolosa nel morbo di Alzheimer
ROSSINI, GAIA
2021/2022
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by synaptic dysfunction, memory loss, neuroinflammation and neuronal death that afflicts over 55 million people worldwide for which the available drugs concentrate their action at the neurotransmitter level. A possible therapeutic alternative can be found in the study of the interaction of the prion protein (PrPC) with the oligomers of Tau (TauOs). This study investigates the role of PrPC in mediating TauOs-induced alterations at the synaptic and cognitive levels by defining whether or not PrPC could represent a new molecular target to prevent cognitive decline in AD. Our PrPKO experimental models demonstrate the efficacy in preventing, contrary to what happens in WT models, the cognitive deficits acutely induced by intracerebroventricularly injected TauOs. Through electrophysiological analysis we confirmed that PrPC also mediates the TauOs-induced impairment of LTP. Biochemical studies have allowed us to confirm, in agreement with what is present in the literature, a different expression of synaptic proteins after treatment with TauOs and an increase in GluR1 receptors. Ultimately we studied the involvement of glial cells in the presence and absence of PrPC, considering that the cognitive impairment induced by AβOs and α-SynOs is associated with an activation of astrocytes and microglia. Our analyses, although not significantly, showed that TauOs activate microglia, but only in the presence of PrPC. In conclusion, the data obtained clearly show that PrPC acts as a mediator of TauOs-induced damage and may therefore represent a new possible therapeutic target for the treatment of AD and other tauopathies.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/16022