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Retinal neurodegeneration and visual dysfunctions have been reported in a majority of Alzheimer's and Parkinson's patients, and, in light of the quest for novel biomarkers for these neurodegenerative proteinopathies, the retina has been receiving increasing attention as an organ for diagnosing, monitoring, and understanding disease. Thinning of retinal layers, abnormalities in vasculature, and protein deposition can be imaged at unprecedented resolution, which offers a unique systems biology view on the cellular and molecular changes underlying these pathologies. It makes the retina not only a promising target for biomarker development, but it also suggests that novel fundamental insights into the pathophysiology of Alzheimer's and Parkinson's disease can be obtained by studying the retina–brain axis. • Retinal changes and visual dysfunctions have been well documented in AD and PD. • Retinal biomarkers may allow early diagnosis and disease monitoring. • The retina offers a view on the cellular and molecular changes underlying AD and PD. • By understanding retina–brain differences, we can grasp AD/PD disease processes. [ABSTRACT FROM AUTHOR]

Vascular endothelial (VE) cadherin can influence vascular morphogenesis. Research findings reveal that VE-cadherin plays a vital role in controlling vascular endothelial growth factor-A-mediated endothelial survival through a pathway that involves the cytoplasmic domain of VE-cadherin, beta-catenin, vascular endothelial growth factor receptor-2 and P13-kinase. A relationship was also established which links the inhibition of normal vascular development with the loss or truncation of VE-cadherin.

Abstract Intravenous and/or intrathecal administration of the anti-folate drug methotrexate is a common chemotherapeutic procedure in childhood leukemia. Therapeutic and prophylactic efficacy of these procedures notwithstanding, the occurrence of late adverse effects remains a cause of clinical concern in leukemia survivors. We propose an experimental mouse model to mimic the impact of methotrexate exposure on brain biochemistry and cell proliferation, as well as behavioral and neurocognitive functioning at adult age. Female C57Bl6/J mouse pups received saline or methotrexate injection (20 mg/kg, i.p.). CSF and serum concentrations of folate metabolites and toxicity makers were analyzed at 4 h, 24 h, and 1 week following injection. Behavioral test battery performance was assessed at adult age (3–4 months). We found acute changes in serum and CSF levels of folate in exposed pups that coincided with increases in CSF Tau, whereas homocysteine in serum and CSF, and CSF levels of pTau were unchanged or remained below detection. In addition, methotrexate injection coincided with diminished hippocampal cell proliferation 1 week after methotrexate injection. At adult age, exposed mice displayed hippocampus-dependent deficits in the Morris water maze, whereas exploration and anxiety-related behaviors were largely unaffected. Particularly during the reference memory (probe) trial after reversal learning, methotrexate-exposed animals were less precise than controls. These findings demonstrate adult neurocognitive sequelae in a mouse model that can be attributed to the biochemical and cellular impact of early-life methotrexate exposure. Highlights • Methotrexate-induced folate depletion associated with acute brain toxicity in mice. • Reduced hippocampal cell proliferation after methotrexate injection. • Early-life methotrexate induces adult cognitive deficits in mice. [ABSTRACT FROM AUTHOR]

• ONC triggers autophagy in the retinotectal system of adult zebrafish. • Injured RGCs induce autophagy in their soma and regrowing axons. • Macroglial cells in the optic nerve/optic tectum display autophagy after ONC. • Systemic autophagy inhibition accelerates axonal regeneration. • Increased mTOR activity might underlie the positive effect of autophagy inhibition. Optic neuropathies comprise a group of disorders in which the axons of retinal ganglion cells (RGCs), the retinal projection neurons conveying visual information to the brain, are damaged. This results in visual impairment or even blindness, which is irreversible as adult mammals lack the capacity to repair or replace injured or lost neurons. Despite intensive research, no efficient treatment to induce axonal regeneration in the central nervous system (CNS) is available yet. Autophagy, the cellular recycling response, was shown repeatedly to be elevated in animal models of optic nerve injury, and both beneficial and detrimental effects have been reported. In this study, we subjected spontaneously regenerating adult zebrafish to optic nerve damage (ONC) and revealed that autophagy is enhanced after optic nerve damage in zebrafish, both in RGC axons and somas, as well as in macroglial cells of the retina, the optic nerve and the visual target areas in the brain. Interestingly, the pattern of the autophagic response in the axons followed the spatiotemporal window of axonal regrowth, which suggests that autophagy is ongoing at the growth cones. Pharmacological inhibition of the recycling pathway resulted in accelerated RGC target reinnervation, possibly linked to increased mechanistic target of rapamycin (mTOR) activity, known to stimulate axonal regrowth. Taken together, these intriguing findings underline that further research is warranted to decipher if modulation of autophagy could be an effective therapeutic method to induce CNS regeneration. [ABSTRACT FROM AUTHOR]

• Aging undeniably impacts central nervous system functioning and repair. • Ignoring the aging context is detrimental for neuroregenerative research. • Aged regenerating animal models are vital in the search for successful therapies. • Spontaneously regenerating animal models inform about cellular and molecular players. In our ever-aging world population, the risk of age-related neuropathies has been increasing, representing both a social and economic burden to society. Since the ability to regenerate in the adult mammalian central nervous system is very limited, brain trauma and neurodegeneration are often permanent. As a consequence, novel scientific challenges have emerged and many research efforts currently focus on triggering repair in the damaged or diseased brain. Nevertheless, stimulating neuroregeneration remains ambitious. Even though important discoveries have been made over the past decades, they did not translate into a therapy yet. Actually, this is not surprising; while these disorders mainly manifest in aged individuals, most of the research is being performed in young animal models. Aging of neurons and their environment, however, greatly affects the central nervous system and its capacity to repair. This review provides a detailed overview of the impact of aging on central nervous system functioning and regeneration potential, both in non-regenerating and spontaneously regenerating animal models. Additionally, we highlight the need for aging animal models with regenerative capacities in the search for neuroreparative strategies. [ABSTRACT FROM AUTHOR]

• X-ray exposure at E7.5 decreases gene and protein expression of Pax6 and Lhx2 at E9. • Irradiation at E7.5 decreases melanogenic gene expression at E11. • Reduced embryonic eye pigmentation at E11 may precede radiation-induced eye defects. • Radiation exposure during neurulation decreases retinal mitosis at E18. Recent studies highlighted a link between ionizing radiation exposure during neurulation and birth defects such as microphthalmos and anophthalmos. Because the mechanisms underlying these defects remain largely unexplored, we irradiated pregnant C57BL/6J mice (1.0 Gy, X-rays) at embryonic day (E)7.5, followed by histological and gene/protein expression analyses at defined days. Irradiation impaired embryonic development at E9 and we observed a delayed pigmentation of the retinal pigment epithelium (RPE) at E11. In addition, a reduced RNA expression and protein abundance of critical eye-development genes (e.g. Pax6 and Lhx2) was observed. Furthermore, a decreased expression of Mitf, Tyr and Tyrp1 supported the radiation-induced perturbation in RPE pigmentation. Finally, via immunostainings for proliferation (Ki67) and mitosis (phosphorylated histone 3), a decreased mitotic index was observed in the E18 retina after exposure at E7.5. Overall, we propose a plausible etiological model for radiation-induced eye-size defects, with RPE melanogenesis as a major determining factor. [ABSTRACT FROM AUTHOR]

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. Upon binding to VEGF- and neuropilin-receptor sub-types, PlGF modulates a range of neural, glial and vascular cell responses that are distinct from VEGF-A. As PlGF expression is selectively associated with pathological angiogenesis and inflammation, its blockade does not affect the healthy vasculature. PlGF actions have been extensively described in tumor biology but more recently there has been accumulating preclinical evidence that indicates that this growth factor could have an important role in retinal diseases. High levels of PlGF have been found in aqueous humor, vitreous and/or retina of patients exhibiting retinopathies, especially those with diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD). Expression of this growth factor seems to correlate closely with many of the key pathogenic features of early and late retinopathy in preclinical models. For example, studies using genetic modification and/or pharmacological treatment to block PlGF in the laser-induced choroidal neovascularization (CNV) model, oxygen-induced retinopathy model, as well as various murine diabetic models, have shown that PlGF deletion or inhibition can reduce neovascularization, retinal leakage, inflammation and gliosis, without affecting vascular development or inducing neuronal degeneration. Moreover, an inhibitory effect of PlGF blockade on retinal scarring in the mouse CNV model has also been recently demonstrated and was found to be unique for PlGF inhibition, as compared to various VEGF inhibition strategies. Together, these preclinical results suggest that anti-PlGF therapy might have advantages over anti-VEGF treatment, and that it may have clinical applications as a standalone treatment or in combination with anti-VEGF. Additional clinical studies are clearly needed to further elucidate the role of PlGF and its potential as a therapeutic target in ocular diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that mitochondrial dysfunction might play a key role in the pathogenesis of age-related neurodegenerative inner retinal diseases such as diabetic retinopathy and glaucoma. Therefore, the present review provides a perspective on the impact of functional mitochondria in the most predominant glial cells of the retina, the Müller cells. Müller cells span the entire thickness of the neuroretina and are in close proximity to retinal cells including the retinal neurons that provides visual signaling to the brain. Among multiple functions, Müller cells are responsible for the removal of neurotransmitters, buffering potassium, and providing neurons with essential metabolites. Thus, Müller cells are responsible for a stable metabolic dialogue in the inner retina and their crucial role in supporting retinal neurons is indisputable. Müller cell functions require considerable energy production and previous literature has primarily emphasized glycolysis as the main energy provider. However, recent studies highlight the need of mitochondrial ATP production to upheld Müller cell functions. Therefore, the present review aims to provide an overview of the current evidence on the impact of mitochondrial functions in Müller cells. [ABSTRACT FROM AUTHOR]

Dysfunction of photoreceptors, retinal pigment epithelium (RPE) or both contribute to the initiation and progression of several outer retinal disorders. Disrupted Müller glia function might additionally subsidize to these diseases. Mitochondrial malfunctioning is importantly associated with outer retina pathologies, which can be classified as primary and secondary mitochondrial disorders. This review highlights the importance of oxidative stress and mitochondrial DNA damage, underlying outer retinal disorders. Indeed, the metabolically active photoreceptors/RPE are highly prone to these hallmarks of mitochondrial dysfunction, indicating that mitochondria represent a weak link in the antioxidant defenses of outer retinal cells. [ABSTRACT FROM AUTHOR]

Considering the increasing number of elderly in the world’s 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. [ABSTRACT FROM AUTHOR]

Due to a prolonged life expectancy worldwide, the incidence of age-related neurodegenerative disorders such as glaucoma is increasing. Glaucoma is the second cause of blindness, resulting from a slow and progressive loss of retinal ganglion cells (RGCs) and their axons. Up to now, intraocular pressure (IOP) reduction is the only treatment modality by which ophthalmologists attempt to control disease progression. However, not all patients benefit from this therapy, and the pathophysiology of glaucoma is not always associated with an elevated IOP. These limitations, together with the multifactorial etiology of glaucoma, urge the pressing medical need for novel and alternative treatment strategies. Such new therapies should focus on preventing or retarding RGC death, but also on repair of injured axons, to ultimately preserve or improve structural and functional connectivity. In this respect, Rho-associated coiled-coil forming protein kinase (ROCK) inhibitors hold a promising potential to become very prominent drugs for future glaucoma treatment. Their field of action in the eye does not seem to be restricted to IOP reduction by targeting the trabecular meshwork or improving filtration surgery outcome. Indeed, over the past years, important progress has been made in elucidating their ability to improve ocular blood flow, to prevent RGC death/increase RGC survival and to retard axonal degeneration or induce proper axonal regeneration. Within this review, we aim to highlight the currently known capacity of ROCK inhibition to promote neuroprotection and regeneration in several in vitro , ex vivo and in vivo experimental glaucoma models. [ABSTRACT FROM AUTHOR]

Highlights: [•] In the nervous system, MMP-2 and -9 actions go far beyond their detrimental roles. [•] MMP-2 and -9 are important in many developmental events in the nervous system. [•] MMP-9 is a key regulator of synaptic plasticity in the healthy adult brain. [•] MMP-2 and -9 promote regeneration and repair of the injured nervous system. [Copyright &y& Elsevier]

Summary: The hypoxia-inducible transcription factors HIF-1α and HIF-2α are activated in hypoxic tumor regions. However, their role in tumorigenesis remains controversial, as tumor growth promoter and suppressor activities have been ascribed to HIF-1α, while the role of HIF-2α remains largely unknown. Here, we show that overexpression of HIF-2α in rat glioma tumors enhances angiogenesis but reduces growth of these tumors, in part by increasing tumor cell apoptosis. Moreover, siRNA knockdown of HIF-2α reduced apoptosis in hypoxic human malignant glioblastoma cells. Furthermore, inhibition of HIF by overexpression of a dominant-negative HIF transgene in glioma cells or HIF-2α deficiency in teratomas reduced vascularization but accelerated growth of these tumor types. These findings urge careful consideration of using HIF inhibitors as cancer therapeutic strategies. [Copyright &y& Elsevier]