Aging impairs the essential contributions of non‐glial progenitors to neurorepair in the dorsal telencephalon of the Killifish Nothobranchius furzeri

Abstract

Age-related neurodegenerative diseases are highly debilitating and incurable pathologies that impinge a high socio-economic burden on our society (El-Hayek et al., 2019). They share a progressive degeneration of neurons, which results in loss of brain function and a heterogeneous array of incapacitating symptoms (Dugger & Dickson, 2017). Therapeutic strategies for brain restoration consist of compensating for neuronal loss by generating new neurons from the existing stem cell pools that can integrate into the existing circuitry. The capacity for neuroregeneration is naturally limited in the adult mammalian brain (Zhao et al., 2016). Neural stem cells

The age factor in optic nerve regeneration: Intrinsic and extrinsic barriers hinder successful recovery in the short‐living killifish

“…Moreover, although no major scarring was observed in young adult killifish, similar to what is reported in young adult zebrafish subjected to ONC (Becker & Becker, 2007 ), we observed a large Gfap‐negative scar area and collagen deposition in 12‐weeks‐, 18‐weeks‐, and 24‐weeks‐old fish, with the most prominent scarring observable at the optic nerve lesion site in old and very old (the oldest) fish. These results are in agreement with findings of Van houcke and coworkers, who reported signs of glial scarring upon stab‐wound lesion in the aged killifish telencephalon (Van houcke et al, 2021 ). Altogether, abnormal activation and/or presence of glial cells might thus trigger the formation of a collagen‐rich glial scar at the site of nerve crush, which has been shown to both physically and chemically prevent outgrowth of axons in mammals (Bradbury & Burnside, 2019 ; Kawano et al, 2012 ; Yang et al, 2020 ) and thus also likely inhibits nerve regeneration in older killifish.…”

Comparative Study in Zebrafish and Medaka Unravels the Mechanisms of Tissue Regeneration

“…These results suggest that RREs might have been repurposed in regeneration-incompetent animals during evolution and only promote tissue repair but not regeneration (Yang and Kang, 2019;. Of note, killifish possess the regenerative capacity in multiple organs, including the heart , fin (Wendler et al, 2015), and brain (Van Houcke et al, 2021) while being phylogenetically closer to medaka (Terzibasi et al, 2007), represent an alternative model for inter-species comparison.…”

“…Fin (Wendler et al, 2015) Heart and fin Brain (Van Houcke et al, 2021) Platyfish (Xiphophorus maculatus)…”

Killifish switch towards mammalian-like regeneration upon aging

“…Interestingly, killifish appear to pay a price for their fast growth and aging. In contrast to zebrafish –that maintain their neuroreparative ability albeit regenerate less efficiently at old age [ 2 – 4 ] –, killifish completely lose their regeneration capacity at old age and are unable to fully recover from CNS injury [ 5 , 6 ]. Using an optic nerve crush injury model in killifish of different ages, we indeed revealed that, in contrast to young fish, aged animals do not regain vision following damage.…”

“…Strikingly, the exaggerated neuroinflammatory events then result in the formation of a long-term glial scar, which has never been shown in any other regeneration-competent model before. Our killiteam at KU Leuven is the first to reveal evidence for such glial scarring within the CNS of aged killifish when subjected to either optic nerve crush or stab injury in the telencephalon [ 5 , 6 ]. This suggests that, in addition to intrinsic factors and altered glial responses, neurorepair in the old killifish CNS is hindered chemically as well as mechanically by glial scar tissue.…”