Monday, October 23, 2023

Zebrafish Can Repair Their Brains. Why Can’t We?

Good news! Amazing stuff!

"... Zebrafish, for example, can continually generate new neurons in their brains, which protects these vertebrates from the ravages of neurological disease and injury. Adult humans, on the other hand, can only make a meager number of new neurons, mostly in the hippocampus (the brain’s memory center), and diseases like Alzheimer’s suppress this production even further. ...
researchers have discovered a mechanism that promotes neurogenesis in the zebrafish brain and has the potential to be activated in people. ...
found a molecule in zebrafish brains called nerve growth factor receptor (NGFR) that nudges stem cells to make new neurons.
NGFR increases neuron production even in zebrafish whose brains show signs of Alzheimer’s disease, which impedes neurogenesis. ..."

From the abstract:
"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. 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."

Zebrafish Can Repair Their Brains. Why Can’t We? | Columbia University Irving Medical Center


Fig. 8: Schematic view of the NGFR/LCN2/SLC22A17-dependent neurogenic switch mechanism in astroglia.


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