Grazia Ilaria Caruso

Ciclo: XXXV

Data inizio: 30/10/2019

Curriculum: Biomedical and Preclinical Biotechnologies

Borsa: UniCT

Titolo tesi: Different polarization of activated microglia in Alzheimer’s disease: targeting SIRT1 to slow down neurodegeneration

Abstract: Alzheimer’s disease (AD) is considered one of the most challenging and lethal neurodegenerative diseases of the century, as currently no effective therapeutic strategies that can prevent or cure the disease are available. Among the main pathogenetic AD markers, neuroinflammation appears since the early phase of AD pathogenesis. In such context, microglia mediate early anti-inflammatory and reparative responses that however cannot be sustained over time, switching into pro-inflammatory and neurotoxic events. Starting from this basis, our project aimed to characterize the early anti-inflammatory and the late pro-inflammatory responses of human microglial HMC3 cell line exposed to Aβ42 oligomers for brief and long time, in order to simulate an acute and a sustained inflammation. In response to Aβ42-induced acute inflammation, Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, was able to mediate the early microglial defensive response through the up-regulation of brain derived neurotrophic factor (BDNF). On the other hand, in a sustained inflammatory context, the addition of melatonin, a multifunctional hormone already known to exert anti-inflammatory functions in the normal and diseased brain, could sustain the anti-inflammatory microglial functions, through up-regulations of SIRT1-BDNF axis. Furthermore, through cross-talk experiments, we demonstrated that conditioned medium collected from anti-inflammatory microglia or pro-inflammatory microglia treated with melatonin, was able to reduce the synaptic impairment of human neuroblastoma SHSY5Y cell line exposed to Aβ42, even in this case through the up-regulation of SIRT1-BDNF axis. Thereafter, we investigated the effects of melatonin in a more complex ex vivo model of organotypic slices cultures, focusing on nucleus basalis of Meynert (nBM) and hippocampus, two areas strongly involved in the impairment of cognitive abilities in AD. The results showed that melatonin supported the survival of cholinergic neurons of nBM and, in the hippocampus challenged with LPS, promoted an anti-inflammatory microglial phenotype, through the up-regulation of BDNF. Finally, considering the prominent role of SIRT1 in the anti-inflammatory microglial response, we tested a delivery SIRT1 system into HMC3 cells using the lipid nanocarriers, large unilamellar vesicles (LUV). After long exposure to Aβ42 oligomers and LUV-SIRT1, we observed an increased mRNA expression of BDNF. In conclusion, our data showed that melatonin has a therapeutic potential in AD neuroinflammation, thanks to its ability to modulate and sustain an anti-inflammatory and protective phenotype, by up regulating SIRT1, that has shown to be an interesting pharmacological target in the management of AD neuroinflammatory process. 

Tutor: M.A. Sortino

Data Conseguimento Titolo: 19/04/2023  

Linkedin: https://it.linkedin.com/in/grazia-ilaria-caruso

Email: grazia.caruso@outlook.it

Periodi all'estero- Sede e data: February – August 2022, Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology Innsbruck, Austria 

Esperienze post-Dottorato ed attuale occupazione: 

• September 2023 – October 2024 
  Study Coordinator – Unità di Cardiologia 
  Ospedale Sant’Orsola Malpighi, Bologna 

• October 2024 – Present 
  Clinical Research Associate (CRA) – IQVIA