Gentile, Antonio (2025) A NUTRACEUTICAL-BASED STRATEGY IN MANAGEMENT AND PREVENTION OF NEURODEGENERATIVE DISEASES. [Tesi di dottorato]

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Abstract

The increase in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, is a growing concern, especially because of the progressively longer life expectancy. This condition is closely linked to activation of the immune system. In particular, microglia—the main immune cells active in the central nervous system (CNS)—play a crucial role in maintaining brain tissue homeostasis. Through pattern recognition receptors they can detect both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). When microglia sense these signals, they release pro-inflammatory cytokines such as TNF-α, IL-1α and C1q. These cytokines induce in astrocytes, which normally support CNS functions, a shift toward a harmful state known as the pro-inflammatory A1 phenotype. A1 astrocytes attack neurons and produce toxic intermediates, thereby damaging the CNS. Conversely, the A2 astrocyte phenotype, promoted by IL-1β and TGF-β, resolves inflammation and supports recovery from injury. In vivo studies have shown that this process can be blocked only by preventing microglial production of pro-inflammatory cytokines. To control this process, Formyl Peptide Receptor 2 (FPR2), expressed by microglia and able to recognize both PAMPs and other inflammatory signals, has been investigated. FPR2 is a promising receptor because it can bind both pro-inflammatory molecules, such as the beta-amyloid peptide (Aβ1-42), and anti-inflammatory compounds, such as the ursolic acid (UA). UA is a compound produced by various plant species that has been shown to reduce inflammation and protect against neurodegenerative damage. The aim of this study is to use industrial wastes from the apple peel extract (ApE), which is rich in UA, as an anti-inflammatory FPR2 agonist to modulate microglial activation and prevent the harmful shift of astrocytes toward the A1 phenotype. This approach seeks to use a natural extract to improve CNS homeostasis, opening the possibility of preventing inflammatory neuronal disorders. Such an approach may not be feasible with conventional drugs because of their side effects.

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