Microglial cell dysregulation in brain aging and neurodegeneration

Abstract

Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide (NO) secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in the reduction of protective activation and the facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegenerative diseases.

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

“…This may be a greater concern as individuals age because the aging process influences the activity of these glial cells in a manner that further shifts microglia towards the 'primed' phenotype, which we hypothesize decreases the brain's resilience 173 . This hypothesis is similar to that of other research groups who have postulated that TBI is lowering the brain's resilience (or 'cognitive reserve') through these microglial-mediated mechanisms 53,54,168,174 .…”

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Recent microarray analysis of human brain tissue has demonstrated a significant age-related upregulation of genes associated with inflammation and immune system activation (Cribbs et al, 2012;Mohan et al, 2016;Nikas, 2013). In animal models of aging, studies have reported an exaggerated response (production of pro-inflammatory cytokines; microglial activation) following treatment with the bacterial endotoxin lipopolysaccharide (LPS) (Matt and Johnson, 2016;von Bernhardi et al, 2015). While LPS-induced neuroinflammation is a far from perfect model of the inflamed aging brain, it does demonstrate the differential response of young and aged neuroimmune cells to an inflammatory stimulus.…”

Els processos neuroinflamatoris associats a les malalties neurodegeneratives. Si se m’inflama el cervell, se m’oblida el teu nom?

“…De fet, es reconeix àmpliament que aquests trastorns sense una preponderància genètica són multifactorials i associats tant amb el seu genoma com amb les condicions ambientals. Encara que les molècules i les vies de senyalització involucrades en la resposta inflamatòria han estat àmpliament caracteritzades, encara no està clar com influeixen en el desenvolupament de malalties neurodegeneratives i la vinculació que tenen amb les condicions mediambientals (Bernhardi, 2015). Aquesta reacció neuroinflamatòria no només englobaria l'activació de cèl·lules glials, sinó també la infiltració de cèl·lules perifèriques del sistema immune (Schwartz, 2013).…”