Introduction
Mitochondrial dysfunction is a hallmark of Alzheimer’s disease (AD), contributing to neurodegeneration through proteotoxic stress and impaired mitochondrial quality control. This study investigates how nicotinamide mononucleotide (NMN), a precursor of NAD+, improves mitochondrial stress response (MSR) and mitigates AD pathology. The study explores the ATF4-dependent mitochondrial unfolded protein response (UPRmt) and its implications for mitochondrial homeostasis and neuroprotection.
Key Findings
Disturbed MSR Profiles in AD Patients:
- Plasma biomarkers such as ATF4, ATF5, CHOP, PINK1, and Parkin were significantly elevated in AD patients compared to healthy controls (HC), indicating disrupted mitochondrial stress response.
- Receiver Operating Characteristic (ROC) analysis revealed strong discriminatory power for these biomarkers in differentiating AD from HC:
- ATF4: AUC = 0.956 (95% CI: 0.920–0.991, p < 0.001).
- PINK1: AUC = 0.952 (95% CI: 0.861–0.982, p < 0.001).
NMN Improves MSR in AD Models:
- NMN treatment increased MSR markers (e.g., ATF4, HSP60) in cell and animal models, restoring mitochondrial protein homeostasis.
- NMN significantly reduced apoptotic markers such as Bax/Bcl-2 ratio and increased antioxidant enzymes (SOD1/2) in vitro (p < 0.01).
Behavioral Improvements in AD Mouse Models:
- NMN supplementation (500 mg/kg/day) improved cognitive functions in 5xFAD mice:
- In the Morris Water Maze test, NMN-treated mice showed shorter escape latency (p < 0.01) and increased platform crossings (p < 0.05).
- Novel Object Recognition (NOR) and Y-Maze tests confirmed improved memory and spatial navigation in NMN-treated mice (p < 0.05).
Reduction of AD Pathology:
- NMN reduced amyloid-β (Aβ) plaque burden in the hippocampus:
- Soluble Aβ1–40 and Aβ1–42 levels decreased significantly (p < 0.001).
- Immunofluorescence analysis revealed a decrease in GFAP-positive astrocytes and microglia activation in NMN-treated mice compared to controls.
ATF4 Dependency of NMN’s Effects:
- ATF4 knockdown abrogated the beneficial effects of NMN, including memory enhancement and Aβ reduction.
- NMN enhanced UPRmt pathways (e.g., ATF4, CLpP) in astrocytes but not in microglia or oligodendrocytes.
Improvement in Synaptic Health and Mitochondrial Homeostasis:
- Synaptic markers (e.g., synaptophysin, PSD-95) increased in NMN-treated mice (p < 0.05).
- NMN-treated hippocampal tissue showed reduced mitochondrial vacuolization and increased ATP production (p < 0.001).
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Implications
Therapeutic Potential of NMN:
- NMN enhances mitochondrial proteostasis through UPRmt activation, delaying AD progression and restoring cognitive functions.
- The results highlight ATF4 as a critical regulator of MSR and a potential target for AD therapy.
Role of Astrocytes in AD Pathology:
- Single-cell RNA sequencing revealed that NMN predominantly altered MSR-related gene expression in astrocytes.
- Astrocyte-specific modulation of MSR may be crucial for mitigating AD-related neuroinflammation and proteotoxic stress.
Diagnostic Biomarkers:
- Plasma MSR markers (ATF4, PINK1) show strong potential for AD diagnosis and disease monitoring.
Conclusion
This study demonstrates that NMN improves mitochondrial quality control and alleviates cognitive and pathological hallmarks of AD in an ATF4-dependent manner. The findings suggest that targeting mitochondrial proteostasis via NAD+ boosters like NMN holds promise for treating AD and potentially other neurodegenerative diseases.
For full details, refer to the original article: https://pubmed.ncbi.nlm.nih.gov/39394148/