Evidence That Aging And Amyloid Promote Microglial Cell Senescence

Abstract

Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer's disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than nondemented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD.

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

“…Telomere length analysis in the aged human brain showed no detectable correlation with age in some studies (Allsopp et al ., 1995), while in others, there was an observed correlation (Nakamura et al ., 2007; Lukens et al ., 2009) which was speculated to be due to change in telomere lengths of a subset of brain cells (Lukens et al ., 2009). In accordance, a study analyzing telomere lengths in pure human microglia isolated from the brain shows significant shortening and predicted propensity for dementia (Flanary et al ., 2007). Here, we show that microglia in G3 mTerc −/− mice display considerable telomere shortening compared to G1 mTerc −/− mice, analogous to results in aged human microglia (Flanary et al ., 2007).…”

“…In accordance, a study analyzing telomere lengths in pure human microglia isolated from the brain shows significant shortening and predicted propensity for dementia (Flanary et al ., 2007). Here, we show that microglia in G3 mTerc −/− mice display considerable telomere shortening compared to G1 mTerc −/− mice, analogous to results in aged human microglia (Flanary et al ., 2007). On the other hand, microglia isolated from young (3 months) and aged (24 months) mice under healthy conditions do not show significant telomere shortening.…”

“…As microglia represent a proliferation‐competent cell population, it is reasonable to hypothesize that self‐renewal and subsequent telomere shortening can alter the proliferative capacity and functionality of microglia. Indeed, microglia telomere shortening has been associated with increasing age and dementia (Flanary et al ., 2007). The proliferative capacity of microglia has shown to be linked to its innate immune response (Shankaran et al ., 2007) and seems to be a critical component in the evolution of chronic neurodegeneration (Gomez‐Nicola et al ., 2013).…”

“…Microglia from aged mice and Alzheimer's mouse models were shown to phagocytose and degrade less amyloid beta peptide (Aβ), thereby contributing to the disease process (Hickman et al ., 2008; Njie et al ., 2012). As dystrophy in microglia is restricted to aged and neurodegenerative brain tissues, it has been proposed to be the consequence of age‐associated telomere shortening and replicative senescence in microglia (Flanary et al ., 2007). …”

Alternations in miRNA Expression in Chronic Stress-Induced Ageing of Leydig Cells

“…Physiological ageing is associated with a progressive decline in cellular functions, an increased risk of major diseases and alteration in gene expression, protein processing and metabolic processes [1]. As evidence indicated in previous studies that accumulation of cellular senescence in some organs or tissues contribute to ageing or several age-related diseases [2,3]. Many different factors have been shown to cause ageing, including lifestyle-related habits, environmental exposures, Reactive Oxygen Species (ROS), and stress.…”