Glaucoma is a multifactorial neurodegenerative disorder affecting 80 million people worldwide. Loss of retinal ganglion cells and degeneration of their axons in the optic nerve are the major pathological hallmarks. Neuroinflammatory processes, inflammatory processes in the central nervous system, have been identified in human glaucoma and in experimental models of the disease. Furthermore, neuroinflammatory responses occur at early stages of experimental glaucoma, and inhibition of certain proinflammatory pathways appears neuroprotective. Here, we summarize the current understanding of neuroinflammation in the central nervous system, with emphasis on events at the optic nerve head during early stages of glaucoma.

Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases. Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa -/- mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture. This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma.

Genetic mouse models for Alzheimer's disease (AD) have been widely used to understand aspects of the biology of the disease, but have had limited success in translating these findings to the clinic. In this review, we discuss the benefits and limitations of existing genetic models and recent advances in technologies (including high throughput sequencing and genome editing) that promise more predictive models. We summarize widely used biomarkers and behavioral tests for mouse models of AD and highlight best practices that will maximize translatability of preclinical findings.

Background: The glaucomas are a common but incompletely understood group of diseases. DBA/2J mice develop a pigment liberating iris disease that ultimately causes elevated intraocular pressure (IOP) and glaucoma. We have shown previously that mutations in two genes, Gpnmb and Tyrp1, initiate the iris disease. However, mechanisms involved in the subsequent IOP elevation and optic nerve degeneration remain unclear. Results: Here we present new mouse strains with Gpnmb and/or Tyrp1 genes of normal function and with a DBA/2J genetic background. These strains do not develop elevated IOP or glaucoma with age. Conclusion: These strains provide much needed controls for studying pathogenic mechanisms of glaucoma using DBA/2J mice. Given the involvement of Gpnmb and/or Tyrp1 in areas such as immunology and tumor development and progression, these strains are also important in other research fields.

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease. Aging is frequently accompanied with frailty and cognitive decline. In recent years, increasing evidence has linked physical inactivity with the development of dementias such as Alzheimer’s disease. In fact, it is recognized that exercise combats frailty and cognitive decline in older adults, but the biological mechanisms involved are not completely known. Understanding the biological changes that trigger cognitive deterioration during aging and the mechanisms by which exercise improves health and brain function is key to ensuring the quality of life of the elderly population and to reducing risk of dementias such as Alzheimer’s disease. Here, we show that the cerebrovascular system in mice significantly deteriorates with age, and the structure and function of the blood brain barrier is progressively compromised. These age-related neurovascular changes are accompanied by neuroinflammation and deficits in common and spontaneous behaviors in mice. We found, however, that exercise from middle to older age preserves the cerebrovascular health, prevents behavioral deficits and reduces the age-related neuroinflammation in the cortex and hippocampus in aged mice. Mice deficient in Apoe, a gene associated with longevity and Alzheimer’s disease, are resistant to the beneficial effects of exercise, suggesting a possible mediating role for APOE in the maintenance and function of the neurovascular system during aging.