Cuciniello, Rossana (2024) Protective effect of dietary CLA against AlCl3-induced neurodegeneration: focus on the molecular mechanisms underlying the downregulation of hallmarks of Alzheimer's disease. [Tesi di dottorato]

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Abstract

The nuclear erythroid-related factor 2 (Nrf2) stands as a pivotal redox-sensitive transcription factor, serving as the master regulator of oxidoreductive and immune homeostasis within cells. In the cytoplasm, Nrf2 forms an association with the inhibitory protein Kelch-like ECH-associated Protein 1 (Keap1). Under conditions of mild oxidative stress, specific cysteine residues in Keap1 undergo alterations that allow newly synthesized Nrf2 to activate the transcription of over 200 target genes implicated in the modulation of key biochemical pathways: mitochondrial function, proteostasis, oxidative and immune homeostasis. The activation of a compensatory mechanism mediated by the Nrf2 pathway may be elicited by its direct modulation by dietary molecules like Conjugated linoleic acid (CLA) or by increasing levels of short-chain fatty acids (SCFAs) following polyphenols, microbial-accessible carbohydrates metabolism by intestinal microbiota. Herein we demonstrate, for the first time, the modulatory ability of CLA on hallmarks (e.g. inflammation, oxidative stress, glucose dysmetabolism) in an animal model of chemically induced AD. Thirty-five male BalbC mice were divided into 5 groups: two AlCl3-intoxicated groups were treated for 5 weeks with low (L) or high (H) Al doses (8 or 100 mg/kg/day in drinking water, respectively; L or H). Two groups of animals, orally supplemented with CLA (600 mg/kg bw/day) for 7 weeks (2 preliminary weeks plus the 5-week treatment with AlCl3; CLA + L, CLA + H) were used to investigate its protective effect, while untreated mice were used as control (Cntr). We provide evidence that mitochondrial dysfunction, Nrf2 alteration, inflammation and Acetylcholinesterase (AChE) hyperactivation can occur even from low exposure. Interestingly, animal pre-treatment with an allometric CLA dose led to significant downregulation of the toxic effects elicited by low or high AlCl3 dose, likely through the activation of an adaptive response. Moreover, we provide data indicating that animal pre-treatment with CLA markedly reduced hyperactivation of compensatory mechanisms (Nrf2 and unfolded protein response) and maladaptive response (inflammation/apoptosis) In the brain cortex likely via a NOX-mediated activation of an adaptive response. In conclusion, presented data highlight the antioxidant and anti-inflammatory effect of CLA, given its ability to modulate Nrf2 activation, representing an intriguing suitable candidate for the treatment of multifactorial disease.

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