CD38 is an ecto-enzyme with NAD+ glycohydrolase activity that plays a central role in regulating cellular NAD+ levels. It is highly expressed in immune cells (B cells, NK cells, macrophages, microglia) and degrades NAD+ to ADP-ribose and cyclic ADP-ribose. CD38 inhibition preserves NAD+ pools, making it a promising therapeutic strategy for neurodegenerative diseases where NAD+ depletion is a common feature.
CD38 Biology and NAD+ Regulation
CD38 Enzymatic Activity
CD38 catalyzes:
NAD+ → ADP-ribose + nicotinamide
NAD+ → cyclic ADP-ribose (cADPR) + nicotinamide
cADPR → ADP-ribose
This activity makes CD38 a major consumer of cellular NAD+, particularly in immune cells and inflamed tissues.
CD38 Expression in Neurodegeneration
Evidence in Neurodegenerative Diseases
Alzheimer's Disease
CD38 expression increases in AD microglia surrounding amyloid plaques
NAD+ depletion in AD brain correlates with cognitive decline
CD38 KO mice show improved cognitive function in AD models
SIRT1 activity (NAD+-dependent) is reduced in AD — CD38 inhibition could restore it
Parkinson's Disease
Microglial CD38 activation contributes to neuroinflammation in PD
NAD+ levels decline in PD substantia nigra
CD38 inhibition protects dopaminergic neurons in MPTP models
Combined with NAD+ precursors (NMN, NR) shows synergy
Amyotrophic Lateral Sclerosis (ALS)
CD38 elevated in ALS microglia and peripheral immune cells
NAD+ depletion in motor neurons contributes to degeneration
CD38 inhibition improves survival in SOD1 mouse models
Clinical trial: CD38 inhibitors being evaluated for ALS
4R-tauopathies show microglial activation with CD38 upregulation
NAD+ metabolism impaired in tauopathy models
CD38 inhibition could reduce neuroinflammation and preserve neuronal NAD+
No direct clinical trials yet — therapeutic potential identified
Frontotemporal Dementia (FTD)
CD38 elevated in FTD brain tissue
NAD+ depletion contributes to transcriptional dysregulation
SIRT1/2 activity reduced — CD38 inhibition could restore deacetylase function
Huntington's Disease
CD38 expression increases in HD microglia
NAD+ levels decline in HD models and patient tissue
CD38 inhibition improves motor function in HD mouse models
Energy metabolism deficits in HD may benefit from NAD+ preservation
Drug Candidates
Clinical-Stage CD38 Inhibitors
Development Pipeline
Mermaid diagram (expand to render)
Challenges
Brain Penetration: Most CD38 inhibitors have limited CNS exposure
Target Engagement: Measuring CD38 inhibition in vivo is challenging
Immune Effects: CD38 inhibition affects immune function — monitoring needed
Therapeutic Strategy
Combination Approach
CD38 inhibitors work best in combination with NAD+ precursors:
Dosing Considerations
Low-dose CD38 inhibitors may be sufficient (e.g., apigenin 50mg daily)
Combined with NAD+ precursor (NMN 250mg daily or NR 300mg daily)
Timing: Morning dosing to align with circadian NAD+ rhythms
Cross-Disease Therapeutic Potential
CD38 inhibition addresses common mechanisms across neurodegenerative diseases:
Clinical Trials
Related NAD+ Trials
Note: While no specific CD38 inhibitor trials are registered for neurodegeneration, the NADAPT study (NCT06162013) evaluates NAD+ replenishment therapy in Parkinsonian syndromes, providing indirect evidence for the CD38 inhibition therapeutic approach.
Cross-Links
Related Mechanisms
[NAD+ Metabolism in Neurodegeneration](/mechanisms/nad-metabolism-neurodegeneration)
[SIRT1 Pathway in Alzheimer's Disease](/mechanisms/sirt1-alzheimer-pathway)
[NAD Signaling in Neurodegeneration](/mechanisms/nad-signaling-neurodegeneration)