Cognitive and behavioral consequences of impaired immunoregulation in aging.
ABSTRACT A hallmark of the aged immune system is impaired immunoregulation of the innate and adaptive immune system in the periphery and also in the central nervous system (CNS). Impaired immunoregulation may predispose older individuals to an increased frequency of peripheral infections with concomitant cognitive and behavioral complications. Thus, normal aging is hypothesized to alter the highly coordinated interactions between the immune system and the brain. In support of this notion, mounting evidence in rodent models indicate that the increased inflammatory status of the brain is associated with increased reactivity of microglia, the innate immune cells of the CNS. Understanding how immunity is affected with age is important because CNS immune cells play an integral role in propagating inflammatory signals that are initiated in the periphery. Increased reactivity of microglia sets the stage for an exaggerated inflammatory cytokine response following activation of the peripheral innate immune system that is paralleled by prolonged sickness, depressive-like complications and cognitive impairment. Moreover, amplified neuroinflammation negatively affects several aspects of neural plasticity (e.g., neurogenesis, long-term potentiation, and dendritic morphology) that can contribute to the severity of neurological complications. The purpose of this review is to discuss several key peripheral and central immune changes that impair the coordinated response between the immune system and the brain and result in behavioral and cognitive deficits.
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ABSTRACT: Cranial radiation therapy causes a progressive decline in cognitive function that is linked to impaired neurogenesis. Chronic inflammation accompanies radiation injury, suggesting that inflammatory processes may contribute to neural stem cell dysfunction. Here, we show that neuroinflammation alone inhibits neurogenesis and that inflammatory blockade with indomethacin, a common nonsteroidal anti-inflammatory drug, restores neurogenesis after endotoxin-induced inflammation and augments neurogenesis after cranial irradiation.Science 01/2004; 302(5651):1760-5. · 31.20 Impact Factor
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ABSTRACT: Microglia are evenly distributed throughout the brain parenchyma. They respond rapidly to a variety of alterations in the microenvironment of the brain and act as sensors for pathological events in the brain. In the present study, we investigated the age-dependent changes in the immunoreactivity and protein level of ionized calcium-binding adapter molecule 1 (Iba-1), a microglial marker, in the CA1 region of the gerbil hippocampus. Iba-1 immunoreactive microglia were detected in the hippocampal CA1 region of the postnatal month 1 (PM 1) group. Iba-1 positive microglia were morphologically inactive between the PM 1 and PM 12 stages. Some Iba-1 immunoreactive microglia were present in the active form in the hippocampal CA1 region of the PM 18 and PM 24 groups. The Iba-1 protein levels in hippocampal CA1 homogenates were decreased in the PM 1 through PM 6 groups and increased in an age-dependent manner thereafter. These results suggest that Iba-1 immunoreactive microglia in the active form were detected in the hippocampal CA1 region in the PM 18 and PM 24 groups. This result may be associated with an age-dependent susceptibility to neurodegenerative diseases associated with the hippocampus.Journal of Veterinary Medical Science 12/2007; 69(11):1131-6. · 0.88 Impact Factor
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ABSTRACT: We examined the lymphocyte subsets and indices of natural killer (NK) cell activity (lytic unit (LU), index of absolute NK cell activity in vivo (ALU), and NK cell activity on a per-cell basis (PCNK)) in 82 people (age, 30-99 years) who were immunologically normal. Although the number of NK cells was maintained throughout the examined age range, the ALU and PCNK values correlated negatively with age. We then examined whether any of the various immunologic parameters, including the function and cell counts of NK cells, T cells, and neutrophils, related to past infectious episodes and death in the follow-up period in 44 elderly subjects (age, 63-98 years). Only low ALU and PCNK values correlated with a past history of severe infection, while low LU, ALU, and PCNK values were the only parameters which correlated with death due to infection during the follow-up period. We propose that human NK cells do not escape the aging process and that a low NK cell function relates to the development of severe infections, which may be fatal, in elderly subjects.Clinical Immunology and Immunopathology 10/1997; 84(3):269-75.