Adult teleost fish such as zebrafish has a widespread regenerative ability, which is unparalleled in the vertebrate clades 16, 17. The heterogeneity of the neurogenic ability across vertebrates is vast. However, the molecular mechanisms of how neural progenitor cells with astroglial identity could be tweaked to become pro-neurogenic despite the prevalent disease pathology that imposes a reactive astroglial state are unknown.
Neurogenesis reduces in Alzheimer’s disease (AD) patients 14, 15, suggesting an intriguing possibility that enhancing the neurogenic plasticity of the brain could improve the age-related neurodegenerative outcomes. Generation and circuit integration of new neurons contribute to the resilience and cognitive abilities of the brain 6, 7, 8, 9, which could offset late-onset neurodegeneration 10, 11, 12, 13. Neurogenic regions are spatially restricted in mammals, which limits the addition of new neurons to the existing circuitry 5. The generation of new neurons in adulthood reduces with vertebrate phylogeny 1, 2, 3, 4. We suggest that enhancing pro-neurogenic astroglial fate may have therapeutic ramifications in AD. Our study suggests that the reactive non-neurogenic astroglia in AD can be coaxed to a pro-neurogenic fate and AD pathology can be alleviated with Ngfr. Comparing transcriptional changes in mouse, zebrafish, and human AD brains for cell intrinsic differential gene expression and weighted gene co-expression networks revealed common altered downstream effectors of NGFR signaling, such as PFKP, which can enhance proliferation and neurogenesis in vitro when blocked. Postmortem human AD hippocampi and 3D human astroglial cultures showed elevated LCN2 levels correlate with reactive gliosis and reduced neurogenesis. Long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Anti-neurogenic effects of Lcn2 was mediated by Slc22a17, blockage of which recapitulated the pro-neurogenicity by Ngfr. Histological analyses of the changes in proliferation and neurogenesis, single-cell transcriptomics, spatial proteomics, and functional knockdown studies showed that the induced expression of Ngfr reduced the reactive astrocyte marker Lipocalin-2 (Lcn2), which we found was sufficient to reduce neurogenesis in astroglia. Ngfr, which promotes neurogenic fate of astroglia during the amyloid pathology-induced neuroregeneration in zebrafish brain, stimulated proliferative and neurogenic outcomes. In this study, we used APP/PS1dE9 mouse model and induced Nerve growth factor receptor ( Ngfr) expression in the hippocampus. However, the molecular mechanisms promoting pro-neurogenic astroglial fate despite AD pathology are unknown. Neurogenesis, crucial for brain resilience, is reduced in Alzheimer’s disease (AD) that induces astroglial reactivity at the expense of the pro-neurogenic potential, and restoring neurogenesis could counteract neurodegenerative pathology.
Npj Regenerative Medicine volume 8, Article number: 33 ( 2023) Nerve growth factor receptor (Ngfr) induces neurogenic plasticity by suppressing reactive astroglial Lcn2/Slc22a17 signaling in Alzheimer’s disease
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