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000259000 1001_ $$0P:(DE-2719)2812737$$aSiddiqui, Tohid$$b0$$eFirst author$$udzne
000259000 245__ $$aNerve growth factor receptor (Ngfr) induces neurogenic plasticity by suppressing reactive astroglial Lcn2/Slc22a17 signaling in Alzheimer's disease.
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000259000 520__ $$aNeurogenesis, crucial for brain resilience, is reduced in Alzheimer's disease (AD) that induces astroglial reactivity at the expense of the pro-neurogenic potential, and restoring neurogenesis could counteract neurodegenerative pathology. However, the molecular mechanisms promoting pro-neurogenic astroglial fate despite AD pathology are unknown. In this study, we used APP/PS1dE9 mouse model and induced Nerve growth factor receptor (Ngfr) expression in the hippocampus. Ngfr, which promotes neurogenic fate of astroglia during the amyloid pathology-induced neuroregeneration in zebrafish brain, stimulated proliferative and neurogenic outcomes. Histological analyses of the changes in proliferation and neurogenesis, single-cell transcriptomics, spatial proteomics, and functional knockdown studies showed that the induced expression of Ngfr reduced the reactive astrocyte marker Lipocalin-2 (Lcn2), which we found was sufficient to reduce neurogenesis in astroglia. Anti-neurogenic effects of Lcn2 was mediated by Slc22a17, blockage of which recapitulated the pro-neurogenicity by Ngfr. Long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Postmortem human AD hippocampi and 3D human astroglial cultures showed elevated LCN2 levels correlate with reactive gliosis and reduced neurogenesis. Comparing transcriptional changes in mouse, zebrafish, and human AD brains for cell intrinsic differential gene expression and weighted gene co-expression networks revealed common altered downstream effectors of NGFR signaling, such as PFKP, which can enhance proliferation and neurogenesis in vitro when blocked. Our study suggests that the reactive non-neurogenic astroglia in AD can be coaxed to a pro-neurogenic fate and AD pathology can be alleviated with Ngfr. We suggest that enhancing pro-neurogenic astroglial fate may have therapeutic ramifications in AD.
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000259000 7001_ $$0P:(DE-2719)2811286$$aCosacak, Mehmet Ilyas$$b1$$udzne
000259000 7001_ $$0P:(DE-2719)2812472$$aPopova, Stanislava$$b2$$udzne
000259000 7001_ $$0P:(DE-2719)2811306$$aBhattarai, Prabesh$$b3$$udzne
000259000 7001_ $$00000-0001-7045-5068$$aYilmaz, Elanur$$b4
000259000 7001_ $$aLee, Annie J$$b5
000259000 7001_ $$00000-0001-8775-8743$$aMin, Yuhao$$b6
000259000 7001_ $$aWang, Xue$$b7
000259000 7001_ $$aAllen, Mariet$$b8
000259000 7001_ $$00000-0003-4070-6756$$aİş, Özkan$$b9
000259000 7001_ $$0P:(DE-2719)9002487$$aAtasavum, Zeynep Tansu$$b10$$udzne
000259000 7001_ $$0P:(DE-2719)9000726$$aRodriguez-Muela, Natalia$$b11$$udzne
000259000 7001_ $$aVardarajan, Badri N$$b12
000259000 7001_ $$aFlaherty, Delaney$$b13
000259000 7001_ $$aTeich, Andrew F$$b14
000259000 7001_ $$aSanta-Maria, Ismael$$b15
000259000 7001_ $$aFreudenberg, Uwe$$b16
000259000 7001_ $$00000-0003-0189-3448$$aWerner, Carsten$$b17
000259000 7001_ $$aTosto, Giuseppe$$b18
000259000 7001_ $$aMayeux, Richard$$b19
000259000 7001_ $$aErtekin-Taner, Nilüfer$$b20
000259000 7001_ $$0P:(DE-2719)2811030$$aKizil, Caghan$$b21$$eLast author$$udzne
000259000 773__ $$0PERI:(DE-600)2879698-6$$a10.1038/s41536-023-00311-5$$gVol. 8, no. 1, p. 33$$n1$$p33$$tnpj regenerative medicine$$v8$$x2057-3995$$y2023
000259000 8564_ $$uhttps://www.nature.com/articles/s41536-023-00311-5
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