CD38 in Neurodegeneration and Neuroinflammation

Abstract

Neurodegenerative diseases are characterized by neuronal degeneration as well as neuroinflammation. While CD38 is strongly expressed in brain cells including neurons, astrocytes as well as microglial cells, the role played by CD38 in neurodegeneration and neuroinflammation remains elusive. Yet, CD38 expression increases as a consequence of aging which is otherwise the primary risk associated with neurodegenerative diseases, and several experimental data demonstrated that CD38 knockout mice are protected from neurodegenerative and neuroinflammatory insults. Moreover, nicotinamide adenine dinucleotide, whose levels are tightly controlled by CD38, is a recognized and potent neuroprotective agent, and NAD supplementation was found to be beneficial against neurodegenerative diseases. 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.

Keywords: ALS.; Alzheimer’s disease; CD38; NAD; Parkinson’s disease; aging; neurodegeneration; neuroinflammation.

Figure 1

Cartoon summarizing current data on CD38 expression and functions in neuronal and glial cells.

Figure 2

Hypothetic role played by CD38 in neurodegeneration and neuroinflammation. Normal or pathological aging is characterized by an increased number of senescent cells in the brain, mostly astrocytes, which adopt a senescence-associated secretory phenotype (SASP) characterized by the release of proinflammatory cytokines and chemokines. These proinflammatory factors increase CD38 expression in astrocytes and microglial cells, leading to (i) amplified release of proinflammatory cytokines and neuroinflammation as well as (ii) NAD depletion due to increased CD38 enzymatic activity that results in reduced activity of the NAD-dependent enzymes sirtuins and PARP, accumulation of DNA damage as well as metabolic dysfunctions and oxidative stress, leading to neuronal impairment and ultimately cell death.