• In a mouse model for blood-brain barrier (BBB) dysfunction, NAD+ levels are low within BBB cells. 
  • NMN prevents age-related BBB leakage, an indicator of BBB dysfunction. 
  • Pretreatment with NMN reduces brain damage caused by stroke, which is linked to BBB damage. 

Our BBB protects our brain from toxins in the bloodstream but deteriorates with aging, which may lead to cognitive impairments and neurodegeneration. Since BBB leakage contributes to diseases like stroke and Alzheimer’s, finding a therapy that preserves BBB function is of critical value to an aging population.

Such a therapy could be NMN, according to the most recent findings of Zhan and colleagues from Peking University in China. As reported in Neuron, the researchers observed low NAD+ levels in a mouse model for age-related BBB dysfunction. Furthermore, NMN prevented BBB dysfunction in this mouse model and aged mice. Moreover, NMN reduced brain damage from stroke, which is linked to BBB damage. 

NMN Preserves the Blood-Brain Barrier

To determine the risk factors involved in BBB disruption during aging, Zhan and colleagues measured genes from human brain samples. They found that a gene for a protein called connexin 43 (CX43) decreased with age. CX43 has multiple BBB-related functions, but how it affects the BBB with aging remains unknown.  

Accordingly, the researchers genetically engineered a mouse lacking CX43. Like aged mice, these CX43-deficient mice had leaky BBBs and exhibited cognitive impairment. Furthermore, the CX43-deficient mice had low NAD+ levels. These findings indicate that CX43 loss contributes to age-related BBB deterioration, which is associated with low intracellular NAD+ concentrations. 

(Zhan et al., 2023 | Neuron) Low NAD+ Levels with BBB Dysfunction. Compared to normal mice (blue), CX43-deficient mice with BBB dysfunction (red) have low NAD+ levels. 

Since NAD+ was depleted in CX43-deficient mice, Zhan and colleagues gave them 100 mg/kg/day of NMN in their drinking water for 12 months. A group of aged mice (18-months-old) was also treated with NMN. The results showed that NMN prevented BBB leakage in both the aged mice and aged CX43-deficient mice. These findings demonstrate that NMN protects the BBB from age-related damage. 

(Zhan et al., 2023 | Neuron) NMN Prevents BBB Dysfunction. Compared to normal aged mice (blue), CX43-deficient aged mice (red) have greater BBB dysfunction (Dye leakage). However, NMN prevents age-related BBB dysfunction in both aged mice (light green) and CX43-deficient aged mice (green).

Since BBB dysfunction is associated with stroke, Zhan and colleagues tested the effect of NMN upon stroke-induced brain damage. To do so, the researchers first pretreated mice with NMN for 5 days. After NMN pretreatment, the researchers occluded one of the major arteries of the brain to trigger a stroke. It was found that NMN reduced the amount of brain damage caused by the stroke, suggesting that NMN protects against stroke.

(Zhan et al., 2023 | Neuron) NMN Reduces Brain Damage from Stroke. Compared to mice not treated with NMN (blue), mice treated with NMN prior to stroke (red) exhibited less brain damage (Infarct volume percentage) upon stroke.

NMN for Protecting the Brain Against Stroke  

Overall, the findings of Zhan and colleagues suggest that NMN prevents age-related BBB decline, which protects against brain damage from stroke. Another study showed that NMN reduced stroke incidence in rats, which could potentially be due to preserving BBB function. Furthermore, NMN may protect BBB cells by reducing oxidative stress — one of the primary drivers of aging.   

Additionally, NMN has previously been shown to protect against brain damage from stroke. In this previous study, NMN was shown to improve the balance of mice after stroke, suggesting that NMN could counter behavioral deficits associated with brain damage. While clinical studies are necessary, these animal studies suggest that NMN could protect the brain against stroke in humans.