Key Points:
- NMN restored NAD+ levels and improved motor performance in Parkinson’s disease (PD) model mice.
- It reduced inflammation, prevented synaptic loss, and lowered harmful brain immune activity (gliosis).
- The benefits were linked to healthier mitochondria and stronger energy production.
- NMN activated key mitochondrial stress response pathways (UPRmt and mitophagy).
- The protective effects required ATF4, a protein that triggers the brain’s mitochondrial repair system.
Effect of NMN Assessed in Parkinson’s Disease Mouse Model
To mimic Parkinson’s disease, mice were given MPTP, a toxin that selectively destroys dopamine-producing neurons.
After the damage was induced, mice received daily injections of NMN (500 mg/kg) for two months. Another group had the ATF4 gene blocked to test its role in NMN’s effects.
Researchers tested:
- Movement (open field, pole, rotarod, and suspension tests)
- NAD+ levels in blood and brain
- Neuronal survival, mitochondrial health, and inflammation markers
Flowchart of NMN injection in MPTP-induced mice model of PD. Mice were given MPTP for 7 days to induce Parkinson-like damage. Then treated daily with NMN (500 mg/kg) for 2 months. Researchers assessed: NAD+ levels in blood and brain, motor behavior (open field, pole, rotarod, and suspension tests), and brain pathology via TH and DAT expression in dopamine pathways.
NMN Improved Motor Function
Mice exposed to MPTP developed movement problems, similar to those seen in Parkinson’s disease. NMN significantly improved:
- Mobility and total distance moved
- Balance and coordination
- Emotional behavior, with less immobility in the suspension test
“Together, these behavioral tests demonstrate that NMN significantly positively affects motor impairment and emotional performance in mice with PD.”
Preserved Dopamine Neurons and Synapses
The MPTP toxin caused a significant loss of dopamine-producing neurons, which is a primary characteristic of Parkinson's disease.
However, NMN demonstrated a strong protective effect on the brain:
- NMN partially prevented loss of tyrosine hydroxylase (TH), a marker of dopamine neurons.
- Preserved dopamine transporter (DAT) levels in key brain regions for movement control (striatum and substantia nigra).
- Helped maintain levels of pre- and post-synaptic proteins, suggesting it protects the vital connections between neurons that are often lost in the disease
This figure shows brain images from mice, with red indicating levels of Dopamine Transporter (DAT) - a marker of healthy dopamine neurons.
Top (WT): The healthy mouse shows a bright red signal, indicating high DAT levels.
Middle (MPTP): The Parkinson's model mouse shows a dim signal, indicating significant DAT loss from toxin-induced damage.
Bottom (MPTP + NMN): After NMN treatment, the red signal is visibly brighter. The study notes that this shows "NMN increased DAT intensity," helping to protect the neurons.
Reduced Brain Inflammation
Chronic neuroinflammation contributes to the progression of PD.
In the MPTP mouse model, NMN treatment significantly suppressed this inflammation:
- Key inflammatory markers (IL-1β, TNF, and NLRP3) were reduced
- Reduced the activation of microglia and astrocytes, the brain's resident immune cells that can cause damage when over-activated
This suggests NMN helped create a more stable and less damaging brain environment.
Restored NAD+ and Mitochondrial Function
The study found that NMN's benefits are strongly tied to its ability to improve mitochondrial function. In the brains of MPTP mice, NMN treatment:
- Increased citrate synthase, a marker for mitochondrial content
- Boosted ATP levels, the energy that mitochondria produce
- Activated key mitochondrial quality control (MQC) pathways, including UPRmt and mitophagy
- Enhanced expression of mitochondrial quality control proteins (ATF4, ATF5, LONP1, PINK1, and Parkin), which help the cell repair or remove damaged mitochondria
Levels of NAD+ were also increased in the blood and brain of the mice.
This graph shows NAD+ levels in a brain region affected by Parkinson’s.
Healthy mice (WT, pink) have normal levels, and NMN boosts them even more (WT + NMN, green).
Mice with Parkinson’s-like damage have much lower NAD+ (MPTP, purple), but NMN treatment restores it (MPTP + NMN, blue), suggesting NMN helps repair the brain’s energy system even under stress.
NMN Requires the ATF4 Pathway to Work
To understand how NMN works, researchers blocked the protein ATF4, a master regulator of the mitochondrial stress response:
When they specifically blocked ATF4 in the brains of the mice, the neuroprotective and motor-improving benefits of NMN were completely eliminated.
This finding demonstrates that the ATF4 pathway is an essential mediator for NMN's neuroprotective effects, meaning NMN appears to work by specifically activating this pathway to shield the brain.
Conclusion
NMN effectively countered key symptoms and pathology of PD.
On a functional level, NMN rescued motor deficits, while on a cellular level, it provided powerful neuroprotection by preventing the death of dopamine neurons and reducing harmful brain inflammation.
These benefits were directly linked to NMN's ability to restore NAD⁺ levels and enhance mitochondrial health through the activation of the ATF4 stress-response pathway.
“Taken together, these results suggested that the administration of NMN attenuated not only MPTP-induced neuroinflammation but also subsequent MPTP-induced neurodegeneration.”
“Treatment with NMN improved MQC and cellular homeostasis in the brains of PD mice by activating UPRmt-mitophagy signaling, suggesting that the neuroprotective effect of NMN may be mediated by the ATF4 pathway.”
“Among the available NAD+ precursors examined, NMN has emerged as a promising therapeutic candidate because of its high bioavailability and minimal toxicity.”
