Jessie Van houcke

Neuroinflammation as Fuel for Axonal Regeneration in the Injured Vertebrate Central Nervous System

Damage to the central nervous system (CNS) is one of the leading causes of morbidity and mortality in elderly, as repair after lesions or neurodegenerative disease usually fails because of the limited capacity of CNS regeneration. The causes underlying this limited regenerative potential are multifactorial, but one critical aspect is neuroinflammation. Although classically considered as harmful, it is now becoming increasingly clear that inflammation can also promote regeneration, if the appropriate context is provided. Here, we review the current knowledge on how acute inflammation is intertwined with axonal regeneration, an important component of CNS repair. After optic nerve or spinal cord injury, inflammatory stimulation and/or modification greatly improve the regenerative outcome in rodents. Moreover, the hypothesis of a beneficial role of inflammation is further supported by evidence from adult zebrafish, which possess the remarkable capability to repair CNS lesions and even restore functionality. Lastly, we shed light on the impact of aging processes on the regenerative capacity in the CNS of mammals and zebrafish. As aging not only affects the CNS, but also the immune system, the regeneration potential is expected to further decline in aged individuals, an element that should definitely be considered in the search for novel therapeutic strategies.

Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system

Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp‐2 and ‐13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp‐2 and ‐9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp‐14 expression decreased during regeneration. Altogether, a phase‐dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron‐intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472–1493, 2016.

The zebrafish as a gerontology model in nervous system aging, disease, and repair

Considering the increasing number of elderly in the worlds population today, developing effective treatments for age-related pathologies is one of the biggest challenges in modern medical research. Age-related neurodegeneration, in particular, significantly impacts important sensory, motor, and cognitive functions, seriously constraining life quality of many patients. Although our understanding of the causal mechanisms of aging has greatly improved in recent years, animal model systems still have much to tell us about this complex process. Zebrafish (Danio rerio) have gained enormous popularity for this research topic over the past decade, since their life span is relatively short but, like humans, they are still subject to gradual aging. In addition, the extensive characterization of its well-conserved molecular and cellular physiology makes the zebrafish an excellent model to unravel the underlying mechanisms of aging, disease, and repair. This review provides a comprehensive overview of the progress made in zebrafish gerontology, with special emphasis on nervous system aging. We review the evidence that classic hallmarks of aging can also be recognized within this small vertebrate, both at the molecular and cellular level. Moreover, we illustrate the high level of similarity with age-associated human pathologies through a survey of the functional deficits that arise as zebrafish age.

Successful optic nerve regeneration in the senescent zebrafish despite age-related decline of cell intrinsic and extrinsic response processes

Dysfunction of the central nervous system (CNS) in neurodegenerative diseases or after brain lesions seriously affects life quality of a growing number of elderly, since the adult CNS lacks the capacity to replace or repair damaged neurons. Despite intensive research efforts, full functional recovery after CNS disease and/or injury remains challenging, especially in an aging environment. As such, there is a rising need for an aging model in which the impact of aging on successful regeneration can be studied. Here, we introduce the senescent zebrafish retinotectal system as a valuable model to elucidate the cellular and molecular processes underlying age-related decline in axonal regeneration capacities. We found both intrinsic and extrinsic response processes to be altered in aged fish. Indeed, expression levels of growth-associated genes are reduced in naive and crushed retinas, and the injury-associated increase in innate immune cell density appears delayed, suggesting retinal inflammaging in old fish. Strikingly, however, despite a clear deceleration in regeneration onset and early axon outgrowth leading to an overall slowing of optic nerve regeneration, reinnervation of the optic tectum and recovery of visual function occurs successfully in the aged zebrafish retinotectal system.

An Antagonistic Axon-Dendrite Interplay Enables Efficient Neuronal Repair in the Adult Zebrafish Central Nervous System

Neural insults and neurodegenerative diseases typically result in permanent functional deficits, making the identification of novel pro-regenerative molecules and mechanisms a primary research topic. Nowadays, neuroregenerative research largely focuses on improving axonal regrowth, leaving the regenerative properties of dendrites largely unstudied. Moreover, whereas developmental studies indicate a strict temporal separation of axogenesis and dendritogenesis and thus suggest a potential interdependency of axonal and dendritic outgrowth, a possible axon-dendrite interaction during regeneration remains unexplored. To unravel the inherent dendritic response of vertebrate neurons undergoing successful axonal regeneration, regeneration-competent adult zebrafish of either sex, subjected to optic nerve crush (ONC), were used. A longitudinal study in which retinal ganglion cell (RGC) dendritic remodeling and axonal regrowth were assessed side-by-side after ONC, revealed that—as during development—RGC axogenesis precedes dendritogenesis during central nervous system (CNS) repair. Moreover, dendrites majorly shrank before the start of axonal regrowth and were only triggered to regrow upon RGC target contact initiation, altogether suggestive for a counteractive interplay between axons and dendrites after neuronal injury. Strikingly, both retinal mechanistic target of rapamycin (mTOR) and broad-spectrum matrix metalloproteinase (MMP) inhibition after ONC consecutively inhibited RGC synapto-dendritic deterioration and axonal regrowth, thus invigorating an antagonistic interplay wherein mature dendrites restrain axonal regrowth. Altogether, this work launches dendritic shrinkage as a prerequisite for efficient axonal regrowth of adult vertebrate neurons, and indicates that molecular/mechanistic analysis of dendritic responses after damage might represent a powerful target-discovery platform for neural repair.

Modelling aging and age-associated pathology in zebrafish

Abstract With the increasing number of active elderly in our society, healthy aging has become a main priority for policy makers, clinicians, and researchers. Although research of the pathophysiological mechanisms underlying aging has taken leaps forward in recent years, developing effective treatments to ensure quality of life up to advanced age remains one of the biggest challenges in biomedical research today. Animal research models are indispensable in solving this complex puzzle, and research using the zebrafish has definitely gained popularity over the past decade. Owing to their relatively short life span, processes of gradual aging can be studied in a reasonable time window, while the extensive characterization of its well-conserved molecular and cellular physiology has delivered a set of most valuable tools and techniques. In this manuscript, we review the current findings from zebrafish gerontology research and point out the striking similarities—and differences—between zebrafish and mammals, which could eventually lead to a better understanding of mechanisms of aging, disease, and repair.