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 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.
| Cell Type |
Expression Level |
Relevance |
| Microglia |
High (activated) |
Neuroinflammation drives CD38 upregulation |
| B cells |
High |
Systemic immune contribution |
| NK cells |
Moderate |
Immune surveillance |
| Neurons |
Low |
Not primary target |
| Astrocytes |
Variable |
Context-dependent |
- 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
- 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
- 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
- CD38 elevated in FTD brain tissue
- NAD+ depletion contributes to transcriptional dysregulation
- SIRT1/2 activity reduced — CD38 inhibition could restore deacetylase function
- 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
| Drug |
Company |
Stage |
Notes |
| 78c |
Academic/Ruth L. Kirschstein |
Preclinical |
Selective CD38 inhibitor, moderate brain penetration |
| Ara-020 |
Academic |
Preclinical |
Potent CD38 inhibitor |
| S010 |
Academic |
Preclinical |
CD38 inhibitor candidate |
| Apigenin |
Natural compound |
Preclinical/clinical |
Flavonoid with CD38 inhibition, used in humans |
| AZD0305 |
AstraZeneca |
Preclinical |
CD38 inhibitor, oncology |
flowchart TD
A["CD38 Inhibitors"] --> B["Preclinical"]
B --> C["Phase 1"]
C --> D["Phase 2"]
D --> E["Phase 3"]
B --> F["78c"]
B --> G["Ara-020"]
B --> H["S010"]
B --> I["Apigenin"]
B --> J["AZD0305"]
F --> K["ALS"]
G --> L["AD/PD"]
I --> M["Various"]
- 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
CD38 inhibitors work best in combination with NAD+ precursors:
| Combination |
Rationale |
Status |
| CD38 inhibitor + NMN |
Inhibits NAD+ consumption + provides substrate |
Preclinical |
| CD38 inhibitor + NR |
Inhibits consumption + alternative precursor |
Preclinical |
| CD38 inhibitor + nicotinamide |
Inhibits consumption + endogenous precursor |
Preclinical |
| CD38 inhibitor + SIRT1 activator |
Dual NAD+ preservation + activation |
Conceptual |
- 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
CD38 inhibition addresses common mechanisms across neurodegenerative diseases:
| Mechanism |
Disease Relevance |
CD38 Inhibition Effect |
| NAD+ depletion |
Universal in neurodegeneration |
Preserves cellular NAD+ pools |
| Microglial activation |
AD, PD, ALS, CBS, PSP |
Reduces inflammatory NAD+ consumption |
| SIRT1/SIRT2 dysfunction |
AD, PD, HD, FTD |
Restores NAD+-dependent deacetylase activity |
| Mitochondrial dysfunction |
PD, ALS, HD |
Supports NAD+-dependent metabolic enzymes |
| DNA repair |
Age-related neurodegeneration |
Maintains PARP activity for repair |
| Trial ID |
Intervention |
Status |
Indication |
| NCT06162013 |
NAD+ precursor (NMN/NR) |
Recruiting |
PD, PSP, Atypical Parkinsonism |
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.
- Roboon J, et al, (2019) CD38 in neurodegenerative diseases
- Zocchi E, et al, (2019) CD38 in age-related neurodegeneration
- Hattori T, et al, (2016) CD38 and its role in the brain
- Quarona V, et al, (2013) Unraveling the contribution of CD38 to neurodegeneration
- Chiollaz M, et al, (2020) CD38 in Alzheimer's disease
- Lee HC, et al, (2014) CD38 and CD157 as therapeutic targets
- Lund FE, et al, (2019) CD38 and calcium signaling in immune cells
- Malavasi F, et al, (2008) CD38: a target for immunotherapeutic approaches
- Ruggieri A, et al, (2015) CD38 in neuroinflammation
- Garlisi CG, et al, (2003) CD38 as a therapeutic target