​​​​​NEURONAL RTP801 IMPAIRS ADULT HIPPOCAMPAL NEUROGENESIS VIA DYSREGULATED NON–CELL-AUTONOMOUS SIGNALING IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is characterized by neuronal stress, neuroinflammation, and circuit dysfunction, which impair adult hippocampal neurogenesis (AHN), a process implicated in the cognition and memory deficits observed in AD. RTP801/REDD1 is a stress-induced inhibitor of mTOR/Akt signaling that is upregulated in AD. Silencing RTP801 in hippocampal neurons and astrocytes prevents cognitive deficits and neuroinflammation; however, the exact mechanisms by which RTP801 contributes to neurodegeneration are not yet fully elucidated.
Here, we investigated whether neuronal RTP801 elevation disrupts neurogenic niche homeostasis in the hippocampus of the 5xFAD mouse model of AD. To do so, we used neuron-specific adeno-associated viral particles to silence RTP801 in 6-month-old wild-type (WT) and 5xFAD mice, using scrambled shRNA as control in both genotypes.
Using proteomics, phosphoproteomics, immunohistochemistry, and morphological analyses, we found that neuronal RTP801 silencing robustly increased Sox2+/GFAP+ neural stem cells and DCX+ progenitors in both WT and 5xFAD mice, indicating enhanced AHN. Proteomic analyses revealed extensive remodeling of the hippocampal proteome, and neuronal RTP801 silencing reverted multiple AD-associated pathways. Phosphoproteomics identified widespread dysregulation of kinase signaling in 5xFAD mice, including GSK3β and MAPK pathways; both largely normalized by neuronal RTP801 silencing. Consistently, RTP801 knockdown restored dentate granule neuron dendritic architecture and corrected AD-associated morphological abnormalities. Mechanistically, neuronal RTP801 modulated BDNF/TrkB signaling in a disease-dependent manner and shifted parvalbumin-positive interneurons toward a normal state associated with restored GABA handling.
Together, these findings identify neuronal RTP801 as a central stress-responsive hub that profoundly impacts the hippocampal neurogenic niche and impairs AHN in AD.