NMN Adenosine Transport Enhancement for Cortical Neuron Senescence Rescue in Alzheimer's Disease

Neuronal NAD+ decline in Alzheimer’s disease follows a spatially heterogeneous pattern, with cortical and hippocampal neurons exhibiting earlier and more severe depletion than subcortical populations due to differential expression of the NMN transporter SLC12A8 (solute carrier family 12, member 8). This hypothesis proposes that enhancing NMN import into cortical neurons via SLC12A8 agonism or direct NMN intranasal delivery, combined with concurrent SIRT1 activation through small-molecule STAC compounds, achieves superior senescence reversal compared to NMN or NR supplementation alone. The mechanistic prediction is that SLC12A8-mediated NMN transport bypasses the rate-limiting steps of extracellular NMN dephosphorylation by ENPP1, directly supplying the neuronal NAD+ salvage pathway. In amyloid-beta oligomer (Aβ42) treated primary cortical neuron cultures, NMN supplementation partially restores mitochondrial membrane potential (ΔΨm) and reduces SA-β-gal positivity, but SLC12A8 overexpression combined with NMN fully recapitulates the non-senescent phenotype. The therapeutic prediction is that intranasal NMN combined with a CNS-penetrant SIRT1 activator (e.g., SRT2104) will demonstrate superior cognitive rescue in 5xFAD mice compared to either monotherapy, with FDG-PET evidence of restored cortical glucose metabolism. This approach targets the NAD±SIRT1-PGC1α axis as the core metabolic rejuvenation pathway while leveraging the cell-type-specific NMN transport mechanism that distinguishes neuronal from glial senescence rescue strategies. The combination addresses both the supply-side (NAD+ precursor delivery) and activity-side (SIRT1 activation) components of the metabolic reprogramming equation, providing a comprehensive intervention for AD-associated neuronal senescence.