Ageing and the Immune Response in the CNS

The ageing brain serves as the background for most neurodegenerative diseases. Brain ageing itself is generally accompanied by cognitive decline. However, several questions on the biology of brain ageing remain to be answered. Interestingly, no species besides humans show progressively drastic neuronal loss and cognitive decline as observed in clinical-grade Alzheimer's disease (AD). The parameters that cause the shift in balance on the delicate nexus between normal and pathological ageing are unknown. Are these changes that occur during ageing merely sporadic or are they programmed by mechanisms of ageing? What causes the specific regionality of neurodegenerative diseases in the brain? To understand these details about ageing-related neurodegenerative conditions, a careful approach to understanding brain ageing and cellular responses to brain ageing is crucial and might render important insights. In this regard, it is important to highlight that brain ageing is still predominantly seen as an outcome of dysfunction of neurons, with studies on glial cells being very limited. As neuro-supportive cells, glial cells might respond to ageing-related changes in neurons as well. The alterations that glial components suffer in the ageing brain, mechanisms that affect glial ageing and how this in turn affects the progression of neuronal ageing, are thus interesting avenues to address. In this chapter, we will address the current theories on brain ageing in view of the age-related changes in the neuroimmune system. This edition first published 201

Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening

Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-))- and late-generation (third-generation G3 and G4 mTerc(-/-)) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced proinflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening