Vitamin D and L-Cysteine as Potential Regulators of Adiponectin in Alzheimer's Disease: A Narrative Review.

PD is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the formation of alpha-synuclein (αSyn) aggregates in the central nervous system (CNS), also known as Lewy bodies. The pathogenicity of the development of these characteristics is yet to be fully understood. This fact, as well as the high social and economic burden () associated with the disease, poses a challenging framework that implies the need for animal models in order to explore possible molecules and pathways involved in the development of the disease. Up to now, two important factors in the development and progression of the disease have been identified—the immune pro-inflammatory response and oxidative damage (; ). The lesions are ultimately caused by oxidative damage due to oxidative imbalance triggered by excess oxygen reactive species (ROS), neuroinflammation, and energetic metabolism impairment (). The gradual accumulation of ROS in neurons increases the secretion of cytokines, microglial activation, and apoptosis (). Possible exogenous sources of ROS include radiation, medicine, metabolites, and toxins (). The endogenic ROS model is based on respiratory chain modulation in the mitochondria (), with a reduction in complex I of the respiratory transport chain (). It is known that complex I inhibitors, such as MPTP, lead to cytotoxic effects on dopaminergic neurons—a reason for using MPTP to induce PD like in animal models (). Gut health also seems to play an important role in the development and progression of PD (; ). Braak et al propose the hypothesis of αSyn accumulation in the enteric nervous system that is afterwards advanced through the vagus nerve to the brain in a process comparable with the advancement of prions (). A more recent hypothesis proposes 2 pathogenic pathways, gut-first and brain-first, with the first being the one described by Braak and the second describing first the appearance of αSyn in the CNS and the progression to the enteric nervous system (ENS) through the vagus (). These hypotheses are supported by the previous identification of αSyn in enteric nervous system, the vagus and glossopharyngeal nerves (; ). The injection of αSyn lysate obtained from a patient with PD in the intestinal wall of a rat leads to migration αSyn through the vagus nerve and subsequently, in connected regions of the brainstem (). Additionally, the vagotomy is associated with reduced odds for developing PD (). Given the importance that gut health plays in the development of the disease, gut microbiota, gut-microbiota metabolites, and proinflammatory molecules are a central focus in unlocking the pathogenesis of PD. One of the most well-known gut metabolites, with demonstrated systemic proinflammatory effect, is trimethylamine N-oxide (TMAO) (). Trimethylamine (TMA) results from the metabolism of choline and carnitine by the phyla (; ; ; ; ). The enzyme cluster implicated in the production of TMA is the CutC/CutD gene cluster that can be found in bacterias that are normaly found in limited abundance in normal gut microbiota, such as , and (). The resulting TMA is then absorbed and oxidized in the liver, by flavin-containing monooxygenase 3 (FMO3) leading to the production of TMAO (). Previously, this TMA/FMO3/TMAO pathway has also been linked with diabetes (), rasing another possibility of influence in PD and cardiovascular diseases through altered glucidic metabolism. The resulting TMAO is then predominantly eliminated in urine (), although in cases of dysbiosis, TMAO can be reduced in the gut back to TMA (). Once in the brain, TMAO activates NF-κB, leading to microglial activation, astrocytic activation and NF-kB phosphorylation, leading to priming the NLRP3 inflammasome and cytokine gene expression (). Cytokines, primarily IL-1β, IL-6 and TNFα, are both produced by and maintain microglial activation (). Mice given dietary TMAO exhibit increased brain aging and cognitive impairment, most likely brought on by increased oxidative stress, mitochondrial dysfunction, and suppression of mTOR signaling in the brain (). Damaged mitochondria are both a of ROS and an for the NLRP3 inflammasome, creating a feedforward loop (). The buildup of ROS leads to increased malondialdehyde (MDA) levels. When combined with the previously mentioned effects, this leads to neuronal cell death, via apoptosis, pyroptosis, and necroptosis (). MPTP is used as a model of PD based on toxicity, by directly inhibiting mitochondrial complex I, leading to NLRP3 inflammasome activation through mitochondrial ROS and microglial activation (; ).