PROBING AND TARGETING MITOCHONDRIA BIOENERGETICS IN NEURODEGENERATION

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Targeting mitochondria of neural stem cells for neuroregeneration

Publication . Ribeiro, Maria Filipe Canas de Matos e Oliveira; Cruz, Susana Zeferino Solá da; Rodrigues, Cecília Maria Pereira

The adult mammalian brains display the capacity to generate new neurons from existing neural stem cells (NSCs) in a process called adult neurogenesis. This process drops sharply throughout ageing and is further impaired in neurodegenerative diseases and other neurological disorders. Curiously, mitochondria and mitochondrial metabolism have been shown to be key regulators of NSC fate. The influence of factors such as ageing, metabolism and diet on brain function is also becoming increasingly recognised. Interestingly, emerging data have supported a crosstalk between the brain and gut microbiota, through the modulation of host metabolism. In the present project, we aimed to dissect the molecular mitochondrial mechanisms responsible for neurogenesis alterations in the context of both neurodegeneration, such as in Alzheimer’s disease (AD), and dietary challenge. Initially, we investigated the impact of amyloid-β (Aβ) peptide, a hallmark of AD, in NSC fate and explored the contribution of mitochondria for Aβ-induced NSC changes. We showed that high levels of Aβ peptide result in mitochondrial signalling disruption, affecting NSC viability, proliferation and differentiation. Importantly, under elevated amyloid burden, an irreversible dysfunction of mitochondrial biogenesis, dynamics and oxidative state was found, precluding any rescue of neurogenesis through mitochondria. We then explored the role of mitochondrial signalling pathways in mediating the regulation of adult neurogenesis following a dietary challenge and subsequent changes in diet-associated gut microbiota. Interestingly, we discovered that animals fed a high-fat choline deficient diet (HFCD) diet display premature increased neurogenesis, which further exhausts the NSC pool for long-term neurogenesis. In fact, HFCD diet stimulated gut dysbiosis, upregulating metabolic pathways of short chain fatty acids (SCFAs), such as propionate and butyrate, in the small intestine and cecum. More importantly, the microbial metabolites enhanced mitochondrial biogenesis and oxidative stress in NSCs, while also promoting early neuronal differentiation through a ROS- and p-ERK1/2-dependent mechanism. Notably, this mitochondrial stressdependent pathway was activated in neurogenic niches of HFCD diet-fed mice. In conclusion, our findings clarify the impact of mitochondrial activity during adult neurogenesis and may prove useful in the development of novel strategies to rescue adult neurogenesis.

2019-10Doctoral thesis

Open access