| First Author | Xiong X | Year | 2024 |
| Journal | Cell Death Dis | Volume | 15 |
| Issue | 10 | Pages | 744 |
| PubMed ID | 39394148 | Mgi Jnum | J:359171 |
| Mgi Id | MGI:7749041 | Doi | 10.1038/s41419-024-07062-1 |
| Citation | Xiong X, et al. (2024) NAD(+)-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer's disease via ATF4-dependent mitochondrial UPR. Cell Death Dis 15(10):744 |
| abstractText | Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer's disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD, explorations to develop a MSR-targeted therapeutic strategy against AD are scarce. We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which NAD(+)-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models. Here, we report dyshomeostasis plasma UPR(mt)-mitophagy-mediated MSR profiles in AD patient samples. NMN restores NAD(+) metabolic profiles and improves MSR through the ATF4-dependent UPR(mt) pathway in AD-related cross-species models. At the organismal level, NAD(+) repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD. Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes. In brief, our work provides evidence that MSR has an active role in the pathogenesis of AD, as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely, bolstering mitochondrial proteostasis by NMN decreases protein aggregation, restores memory performance, and delays disease progression, ultimately translating to increased healthspan. |
