Project ID NS-MH2023_33


Co Supervisor 1A IoPPN/Basic and Clinical NeuroscienceWebsite

Co Supervisor 1B IoPPN/Basic and Clinical NeuroscienceWebsite

Investigating the link between autophagy and neuroinflammation in Alzheimer’s disease

Autophagy is a self-degradation mechanism necessary to clear aggregate prone proteins that accumulate in neurodegenerative diseases such as in Alzheimer’s disease (AD). For this reason, investigating the mechanisms that regulate autophagy are currently explored as potential therapeutic targets.

While less characterized, autophagy is also a fine regulator of both innate and adaptive immunity. AD is characterized by neuroinflammation and by an increase in reactive astrocytes. The aim of this project is to investigate the link between autophagy and astrocytic inflammatory responses in AD.

In year 1, we will use primary mouse astrocyte cultures to investigate how autophagy can modulate the astrocyte reaction in response to AD-relevant stimuli. We will modulate autophagy, either pharmacologically using drugs or genetically using siRNAs. Western blotting, ELISA and qPCR will measure changes in reactive astrocyte markers and proinflammatory factors.

In year 2, we will explore drugs that induce autophagy as potential treatments to inhibit astrocyte reactivity and its impact on neuronal toxicity. We will examine neuronal and synaptic health in astrocyte-neuron co-cultures.

To validate our data in a relevant ex vivo model, in years 2 and 3, we will use organotypic brain slice cultures, where autophagy will be modulated pharmacologically or genetically, using either drugs or adenoviruses respectively. Its effect in astrocytes, neurons and microglia will be investigated.

This project will shed light into the role of autophagy in glial cells and its contribution to neuroinflammation in AD. We will provide proof of principle for the inhibition of autophagy as a target to modulate neuroinflammation in AD brain.

This project will combine the expertise of Maria Jimenez-Sanchez on autophagy and Beatriz Gomez Perez-Nievas on AD. Both groups shared an interest on the contribution of astrocytes to disease pathology.

Representative Publications

Sung K and Jimenez-Sanchez M. Autophagy in astrocytes and its implications in neurodegeneration. J Mol Biol. 2020 Apr 3;432(8)

Perez-Nievas BG*, Johnson L, Beltran-Lobo P, Hughes MM, Gammallieri L, Tarsitano F, Myszczynska MA, Vazquez-Villasenor I, Jimenez-Sanchez M, Troakes C, Wharton SB, Ferraiuolo L, Noble W*. Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity. J Neuroinflammation. 2021 Dec 28;18(1):306. doi: 10.1186/s12974-021-02371-0.