Propionate, a major short-chain fatty acid, is produced by fermentation of dietary carbohydrates by the gut microbiota. It plays an important role in maintaining the health and proper functioning of the brain and in protecting against neuroinflammation and neurodegenerative diseases (NDD), such as Alzheimer’s disease. These roles of propionate are potentially mediated by endocrine, immune, vagal, and humoral pathways. In contrast, excessive levels of propionate can result from vitamin B12 deficiency in the elderly and other causes and be toxic, leading to propionic acidemia, hyperammonemia, motor impairments, and dementia. In addition to the microbiota, other potential sources of propionate include the diet, where it is used as a food preservative, and in medical treatments, such as valproic acid. Propionate and propionate-enhancing pre/probiotics, diet, and fecal transplantation can be effective treatments for NDD, but measures should also be taken to prevent propionate toxicity.

Future studies and reviews should further investigate the roles and mechanisms of propionate in the normal functioning of the brain and protection against aging and NDD. Although the gut microbiota is known to be the major source of propionate, how gender, aging, diet, medical treatment, and NDD affect the microbiota and propionate production and metabolism needs further exploration. The roles of FFAR activation, HDAC inhibition, protein (histone) propionylation, and anti-inflammatory signaling in propionate-mediated effects should be further understood. In addition, the causes and mechanisms of propionate toxicity, including insulin resistance, mitochondrial dysfunction, hyperammonemia, and cognitive and motor impairment need clarification. Finally, the effectiveness of exogenous propionate and propionate-enhancing pre/probiotics, diet, and fecal transplantation in the prevention or treatment of various NDD should be further evaluated.
Potential topics include, but are not limited to:

- Assessing the roles of propionate in the health and maintenance of proper functioning of the brain, including maintaining neurons, synapses, and the BBB and protecting against neuroinflammation, proteinopathies (Abeta/tau), cognitive and motor impairment, and NDD.

- Mechanisms of propionate in maintaining health, including activation of FFAR, inhibition of HDAC, protein (histone) propionlyation, and suppression of inflammation signaling processes.
- Assessing the effect of gender, aging, diet, medical treatments, and disease in determining circulating and central propionate levels.

- Exploring the molecular and neurocognitive pathways through which propionate interacts with the aging brain and neurodegenerative diseases, with a focus on Alzheimer’s disease, to clarify its role in maintaining neurohealth and potentially slowing or preventing disease progression.

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Frontiers in Aging Neuroscience

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