Abstract
Aging is the main risk factor for Alzheimer’s disease (AD); however, the aspects of the aging process that predispose the brain to the development of AD are largely unknown. Astrocytes perform a myriad of functions in the central nervous system to maintain homeostasis and support neuronal function. In vitro, human astrocytes are highly sensitive to oxidative stress and trigger a senescence program when faced with multiple types of stress. In order to determine whether senescent astrocytes appear in vivo, brain tissue from aged individuals and patients with AD was examined for the presence of senescent astrocytes using p16INK4a and matrix metalloproteinase-1 (MMP-1) expression as markers of senescence. Compared with fetal tissue samples (n = 4), a significant increase in p16INK4a-positive astrocytes was observed in subjects aged 35 to 50 years (n = 6; P = 0.02) and 78 to 90 years (n = 11; P<10−6). In addition, the frontal cortex of AD patients (n = 15) harbored a significantly greater burden of p16INK4a-positive astrocytes compared with non-AD adult control subjects of similar ages (n = 25; P = 0.02) and fetal controls (n = 4; P<10−7). Consistent with the senescent nature of the p16INK4a-positive astrocytes, increased metalloproteinase MMP-1 correlated with p16INK4a. In vitro, beta-amyloid 1–42 (Aβ1–42) triggered senescence, driving the expression of p16INK4a and senescence-associated beta-galactosidase. In addition, we found that senescent astrocytes produce a number of inflammatory cytokines including interleukin-6 (IL-6), which seems to be regulated by p38MAPK. We propose that an accumulation of p16INK4a-positive senescent astrocytes may link increased age and increased risk for sporadic AD.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–80% of all cases [1]
We found that exposure of astrocytes to Ab1–42 triggers senescence and that senescent astrocytes produce high quantities of interleukin-6 (IL-6), a cytokine known to be increased in the CNS of AD patients [18]
Ab1-42 Peptide Leads to Astrocyte Senescence The mechanisms of Ab-induced neurotoxicity are not fully understood; recent studies suggest a role for nonfibrillar soluble oligomers of Ab in the deleterious effects of Ab on synaptic plasticity and learned behavior [19,20,21,22]
Summary
Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–80% of all cases [1]. Senescent cells increase with age in several tissues [5], little is known about the potential appearance of senescent cells in the brain. It was once thought that senescent cells lack function, it is known that senescent cells are functionally altered. They secrete cytokines and proteases that profoundly affect neighboring cells, and may contribute to age-related declines in organ function [7]. The SASP is characterized by the expression of a complex mixture of factors including reactive cytokines and proteases that create a proinflammatory microenvironment. The relevance of senescent cells to the aging process has been demonstrated by the phenotypic improvement observed following the targeted removal of senescent cells in a progeroid mouse model [9]
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