Reviewing CD38 in Neurodegeneration and Neuroinflammation

Age-related upregulation of CD38 is quite closely related to the decline of NAD+ levels in mitochondria. That in turn causes some fraction of the age-related loss of mitochondrial quality control and mitochondrial function. As mitochondria are the power plants of the cell, providing chemical energy store molecules (adenosine triphosphate, ATP) to power cellular operations, this causes a broad range of issues in tissues throughout the body. Mitochondrial decline is particularly influential in the aging of the brain, given the high energy demands of that organ.

Due to the lack of effective treatment to at least slow down the neurodegenerative process, neurodegenerative diseases (NDDs) are still an unmet medical need. Most high-profile clinical trials for NDDs led to inefficacious results, suggesting that novel approaches to treat these pathologies are needed. Targeting NDDs through the prism of aging is one of such approach. Indeed, the primary risk factor associated with NDDs, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease is aging. Consequently, it is tempting to study age-related dysfunctions that could favor or be instrumental in the neurodegenerative process.

Reduced nicotinamide adenine dinucleotide (NAD) levels might be one of these age-related dysfunctions influencing neurodegeneration. Indeed, NAD levels were found to decrease as a consequence of aging, including in the human brain and cerebrospinal fluid (CSF), while NAD was found to be a potent neuroprotective and anti-inflammatory molecule. The reason as to why NAD levels are reduced as a consequence of aging remained elusive until the discovery in 2016 that expression of CD38, the main enzyme responsible for NAD degradation, increased as a consequence of aging, thus explaining age-related NAD decline. Moreover, CD38 deletion was found to repress neurodegeneration and neuroinflammation in experimental models of NDDs.

However, CD38 biology is complex and not restricted to its NAD-degrading ability. The aims of this review are to summarize the physiological role played by CD38 in the brain, present the arguments indicating the involvement of CD38 in neurodegeneration and neuroinflammation, and to discuss these observations in light of CD38 complex biology.

Link: https://doi.org/10.3390/cells9020471

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