Aging‐dependent changes of microglial cells and their relevance for neurodegenerative disorders

Abstract

J. Neurochem. (2010) 112, 1099–1114. Abstract Among multiple structural and functional brain changes, aging is accompanied by an increase of inflammatory signaling in the nervous system as well as a dysfunction of the immune system elsewhere. Although the long‐held view that aging involves neurocognitive impairment is now dismissed, aging is a major risk factor for neurodegenerative diseases such as Alzheimer`s disease, Parkinson`s disease and Huntington’s disease, among others. There are many age‐related changes affecting the brain, contributing both to certain declining in function and increased frailty, which could singly and collectively affect neuronal viability and vulnerability. Among those changes, both inflammatory responses in aged brains and the altered regulation of toll like receptors, which appears to be relevant for understanding susceptibility to neurodegenerative processes, are linked to pathogenic mechanisms of several diseases. Here, we review how aging and pro‐inflammatory environment could modulate microglial phenotype and its reactivity and contribute to the genesis of neurodegenerative processes. Data support our idea that age‐related microglial cell changes, by inducing cytotoxicity in contrast to neuroprotection, could contribute to the onset of neurodegenerative changes. This view can have important implications for the development of new therapeutic approaches.

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

“…Importantly, stereological, morphological, and flow cytometric analyses of microglial cells showed that the number of microglia with activated morphology and the ratio of CD40 expressing microglia was higher in Cnr1 −/− than in Cnr1 +/+ mice. During aging, an increase in the expression levels of proinflammatory cytokines takes place in the brain (6). We detected a significant increase in the expression of IL-6 in 12-moold Cnr1 −/− mice, whereas the expression of IL-1β, IL-6, or TNF did not differ between 2-mo-old and 12-mo-old wild-type animals, in accordance with previous reports (38).…”

“…Which factors influence the onset and progression of the learning and memory deficits has not been understood yet, but it is hypothesized that the balance between physical, chemical, and biological stressors and antistress responses play a crucial role (3). The immune system is an important element of the antistress system, and it is thought enhanced immune responses play a significant role in the aging process (4)(5)(6).…”

Learning and memory … and the immune system

“…All of the body's immune organs are innervated to some degree, and unimpaired neurotransmission is essential for both initiation and termination of immune responses. For example, sympathetic innervation of the bone marrow is required for recruitment of immune cells from the hematopoietic reservoir during infection (Katayama et al 1990;Spiegel et al 2007;von Bernhardi et al 2010). On the other hand, neuronal control through the vagus nerve serves to suppress inflammation in response to endotoxin (Borovikova et al 2000;Steinman 2004;Pavlov and Tracey 2012).…”

“…Despite their great functional diversity, cytokines in the nervous system have earned an unfortunate reputation through their observed association with inflammation or sickness behavior (Kelley et al 2003;Dantzer et al 2008;Godbout et al 2008;Huang et al 2008). Studies investigating the role of inflammation in aging or pathologye.g., inflammation/infection, neurodegeneration, depressionare numerous and have been reviewed extensively by others (Lucin and Wyss-Coray 2009;von Bernhardi et al 2010;Kohman and Rhodes 2013;McCusker and Kelley 2013). On the other hand, the literature regarding the role of cytokines in homeostatic brain function is slower to accumulate.…”

The endocannabinoid system in normal and pathological brain ageing

“…Moreover, senescent microglia are less functional because they have serious autophagic dysfunction [148]. It is thought the reduced autophagy combined with an enhanced pro-inflammatory character leads to enhanced neurotoxicity and contributes to neurodegenerative changes [149,150]. On the basis of significant contribution of immune system activity to the development of cognitive deficits, it was suggested that rejuvenation of immunity could reverse age-related cognitive deficits [151].…”