Peter van Wijngaarden

M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination

The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell–derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration.

Rejuvenation of Regeneration in the Aging Central Nervous System

Remyelination is a regenerative process in the central nervous system (CNS) that produces new myelin sheaths from adult stem cells. The decline in remyelination that occurs with advancing age poses a significant barrier to therapy in the CNS, particularly for long-term demyelinating diseases such as multiple sclerosis (MS). Here we show that remyelination of experimentally induced demyelination is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis. Restored remyelination in old animals involves recruitment to the repairing lesions of blood-derived monocytes from the young parabiotic partner, and preventing this recruitment partially inhibits rejuvenation of remyelination. These data suggest that enhanced remyelinating activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life.

Genetic susceptibility to retinopathy of prematurity : the evidence from clinical and experimental animal studies

Despite advances in management and treatment, retinopathy of prematurity remains a major cause of childhood blindness. Evidence for a genetic basis for susceptibility to retinopathy of prematurity is examined, including the influences of sex, ethnicity, and ocular pigmentation. The role of polymorphisms is explored in the genes for vascular endothelial growth factor and insulin-like growth factor-1, and of mutations in the Norrie disease gene. Insights into the genetic basis of retinopathy of prematurity provided by the animal model of oxygen induced retinopathy are examined. Evidence for a genetic component for susceptibility to retinopathy of prematurity is strong, although the molecular identity of the gene or genes involved remains uncertain.

Ageing stem and progenitor cells: implications for rejuvenation of the central nervous system

The growing burden of the rapidly ageing global population has reinvigorated interest in the science of ageing and rejuvenation. Among organ systems, rejuvenation of the central nervous system (CNS) is arguably the most complex and challenging of tasks owing, among other things, to its startling structural and functional complexity and its restricted capacity for repair. Thus, the prospect of meaningful rejuvenation of the CNS has seemed an impossible goal; however, advances in stem cell science are beginning to challenge this assumption. This Review outlines these advances with a focus on ageing and rejuvenation of key endogenous stem and progenitor cell compartments in the CNS. Insights gleaned from studies of model organisms, chiefly rodents, will be considered in parallel with human studies.

Emerging ocular biomarkers of Alzheimer disease

Interest in reliable biomarkers of Alzheimer disease, the leading cause of dementia, has been fuelled by challenges in diagnosing the disease and monitoring disease progression as well as the response to therapy. A range of ocular manifestations of Alzheimer disease, including retinal and lens amyloid‐beta accumulation, retinal nerve fiber layer loss, and retinal vascular changes, have been proposed as potential biomarkers of the disease. Herein, we examine the evidence regarding the potential value of these ocular biomarkers of Alzheimer disease.

Recruitment and Testing Protocol in the National Eye Health Survey: A Population-Based Eye Study in Australia

ABSTRACT Purpose: To present the recruitment and testing methodology of the National Eye Health Survey (NEHS), a population-based study that aimed to determine the prevalence and causes of vision impairment and blindness in Australia. Methods: Non-Indigenous Australians aged 50 years and older and Indigenous Australians aged 40 years and older were recruited using a door-to-door approach from 30 randomly selected geographical areas, stratified by remoteness. Participants underwent a vision examination, anterior segment assessment, intraocular pressure testing, perimetry, and fundus photography. Results: In total, recruiters approached 23,235 residences, and 11,883 residents were successfully contacted (51.1%). Of these, 6760 (56.9%) were deemed eligible and 5764 agreed to participate (positive response rate = 85.3%). Of those who agreed, 4836 residents attended the examination (4836/6760 = 71.5%). This included 1738 Indigenous Australians (41.1% male) aged 40–92 years (mean ± standard deviation = 55.0 ± 10.0 years) and 3098 non-Indigenous Australians (46.4% male), aged 50–98 years (mean ± standard deviation = 66.6 ± 9.7 years). Conclusions: The NEHS achieved an excellent positive response rate, and the data collected from 4836 Australians will provide the first population-based national estimate of the prevalence of vision impairment and blindness. This data will guide future economic analysis, policy formulation, and eye health service delivery in Australia.

Sampling methodology and site selection in the National Eye Health Survey (NEHS): an Australian population-based prevalence study

This paper presents the sampling methodology of the National Eye Health Survey that aimed to determine the prevalence of vision impairment and blindness in Australia.

Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

Summary The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfbret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

Exercise reverses age-related vulnerability of the retina to injury by preventing complement-mediated synapse elimination via a BDNF-dependent pathway

Retinal ganglion cells (RGCs) become increasingly vulnerable to injury with advancing age. We recently showed that this vulnerability can be strongly modified in mice by exercise. However, the characteristics and underlying mechanisms of retinal protection with exercise remain unknown. Hence, the aim of this study was to investigate cellular changes associated with exercise‐induced protection of aging retinal cells and the role of local and peripheral trophic signalling in mediating these effects. We focussed on two molecules that are thought to play key roles in mediating beneficial effects of exercise: brain‐derived neurotrophic factor (BDNF) and AMP‐activated protein kinase (AMPK). In middle‐aged (12 months old) C57BL/6J mice, we found that exercise protected RGCs against dysfunction and cell loss after an acute injury induced by elevation of intra‐ocular pressure. This was associated with preservation of inner retinal synapses and reduced synaptic complement deposition. Retinal expression of BDNF was not upregulated in response to exercise alone. Rather, exercise maintained BDNF levels in the retina, which were decreased postinjury in nonexercised animals. Confirming a critical role for BDNF, we found that blocking BDNF signalling during exercise by pharmacological means or genetic knock‐down suppressed the functional protection of RGCs afforded by exercise. Protection of RGCs with exercise was independent of activation of AMPK in either retina or skeletal muscle. Our data support a previously unidentified mechanism in which exercise prevents loss of BDNF in the retina after injury and preserves neuronal function and survival by preventing complement‐mediated elimination of synapses.

The Prevalence and Causes of Vision Loss in Indigenous and Non-Indigenous Australians: The National Eye Health Survey

PURPOSE To conduct a nationwide survey on the prevalence and causes of vision loss in Indigenous and non-Indigenous Australians. DESIGN Nationwide, cross-sectional, population-based survey. PARTICIPANTS Indigenous Australians aged 40 years or older and non-Indigenous Australians aged 50 years and older. METHODS Multistage random-cluster sampling was used to select 3098 non-Indigenous Australians and 1738 Indigenous Australians from 30 sites across 5 remoteness strata (response rate of 71.5%). Sociodemographic and health data were collected using an interviewer-administered questionnaire. Trained examiners conducted standardized eye examinations, including visual acuity, perimetry, slit-lamp examination, intraocular pressure, and fundus photography. The prevalence and main causes of bilateral presenting vision loss (visual acuity <6/12 in the better eye) were determined, and risk factors were identified. MAIN OUTCOME MEASURES Prevalence and main causes of vision loss. RESULTS The overall prevalence of vision loss in Australia was 6.6% (95% confidence interval [CI], 5.4-7.8). The prevalence of vision loss was 11.2% (95% CI, 9.5-13.1) in Indigenous Australians and 6.5% (95% CI, 5.3-7.9) in non-Indigenous Australians. Vision loss was 2.8 times more prevalent in Indigenous Australians than in non-Indigenous Australians after age and gender adjustment (17.7%, 95% CI, 14.5-21.0 vs. 6.4%, 95% CI, 5.2-7.6, P < 0.001). In non-Indigenous Australians, the leading causes of vision loss were uncorrected refractive error (61.3%), cataract (13.2%), and age-related macular degeneration (10.3%). In Indigenous Australians, the leading causes of vision loss were uncorrected refractive error (60.8%), cataract (20.1%), and diabetic retinopathy (5.2%). In non-Indigenous Australians, increasing age (odds ratio [OR], 1.72 per decade) and having not had an eye examination within the past year (OR, 1.61) were risk factors for vision loss. Risk factors in Indigenous Australians included older age (OR, 1.61 per decade), remoteness (OR, 2.02), gender (OR, 0.60 for men), and diabetes in combination with never having had an eye examination (OR, 14.47). CONCLUSIONS Vision loss is more prevalent in Indigenous Australians than in non-Indigenous Australians, highlighting that improvements in eye healthcare in Indigenous communities are required. The leading causes of vision loss were uncorrected refractive error and cataract, which are readily treatable. Other countries with Indigenous communities may benefit from conducting similar surveys of Indigenous and non-Indigenous populations.