Neurogenic induction by Ngfr reduces reactive astrocytic Lcn2/Slc22a17 signalling, amyloid deposition and Tau phosphorylation

Siddiqui, T.; Cosacak, M. I.; popova, S.; Bhattarai, P.; Santa-Maria, I.; tosto, g.; Kizil, C.

doi:10.1101/2022.08.20.504608

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bioRxiv · 10.1101/2022.08.20.504608

Neurogenic induction by Ngfr reduces reactive astrocytic Lcn2/Slc22a17 signalling, amyloid deposition and Tau phosphorylation

Siddiqui, T.·Cosacak, M. I.·popova, S.·Bhattarai, P.·Santa-Maria, I.·tosto, g.·Kizil, C.

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Abstract

Neurogenesis relates to the brain resilience and is reduced in Alzheimers disease (AD). Restoring healthy levels of neurogenesis could have beneficial effects for coping with neurodegeneration. However, molecular mechanisms that could enhance neurogenesis from astroglial progenitors in AD pathology are largely unknown. We used lentiviruses to express Ngfr in the hippocampus of the APP/PS1dE9 mouse model of AD, histologically analyzed the changes in proliferation of neural stem cells and neurogenesis; performed single-cell transcriptomics, spatial proteomics, and functional knockdown studies. We found that expression of Ngfr, a neurogenic determinant in pathology-induced neuroregeneration in zebrafish, stimulated proliferative and neurogenic outcome in the APP/PS1dE9 AD mouse model. Ngfr suppressed reactive astrocyte marker Lipocalin-2 (Lcn2) in astroglia. Blockage of Lcn2 receptor, Slc22a17, recapitulated the neurogenic effects of NGFR, and long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Furthermore, immunostaining on postmortem human hippocampi with AD or primary age-related Tauopathy and 3D human astroglial cultures showed that elevated LCN2 levels correlate with gliosis. By comparing transcriptional changes in mouse hippocampus, zebrafish brain, and human AD brains in terms of cell intrinsic differential gene expression analyses as well as weighted gene co-expression network analysis, we observed common potential downstream effectors of NGFR signaling, C4B and PFKP, that are relevant to AD. Our study links the regulatory role of an autocrine molecular mechanism in astroglia to the neurogenic ability and modulatory effects on amyloid and tau phosphorylation, opening new research avenues and suggesting that neurogenesis-oriented therapeutic approaches could be a potential clinical intervention for AD.

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Siddiqui, T., Cosacak, M. I., popova, S., Bhattarai, P., Santa-Maria, I., tosto, g., Kizil, C.. 2022-08-21. Neurogenic induction by Ngfr reduces reactive astrocytic Lcn2/Slc22a17 signalling, amyloid deposition and Tau phosphorylation. https://doi.org/10.1101/2022.08.20.504608

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