Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

BACKGROUND: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD). METHODS: In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. RESULTS: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. CONCLUSIONS: Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife

Transforming growth factor-beta1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix

Previous studies from our laboratory have shown the ME7 model of murine scrapie to be accompanied by an atypical inflammatory response that is characterized by marked astroglial and microglial activation but also by the lack of significant expression of the pro-inflammatory cytokines interleukin (IL)-1? and IL-6. The aim of this study was to determine whether, in the absence of IL-1? and IL-6, tumour necrosis factor (TNF)-? may play an equivalent pro-inflammatory role, or if an anti-inflammatory cytokine profile dominates. We have used competitive polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) to determine the levels of TNF-?, IL-10 and transforming growth factor (TGF)-?1 in the ME7 model, using their expression in lipopolysaccharide (LPS)-induced acute inflammation as a positive control. Levels of mRNA were elevated for all three cytokines during acute inflammation, while TGF-?1 mRNA alone was significantly elevated in ME7-injected brains. Similarly, by ELISA, we detected elevated IL-10, TNF-? and TGF-?1 in LPS-injected animals but only significant elevation of TGF-?1 in ME7-injected animals. An increase in laminin and collagen IV deposition around blood vessels was also observed and is consistent with up-regulation by active TGF-?1. These findings suggest that TGF-?1 may play a central role in maintenance of an atypical microglial phenotype and may also be involved in vascular and extracellular matrix change

TGF-1 and TGF-2 expression after traumatic human spinal cord injury

TGF-beta1 and TGF-beta2 expression after traumatic human spinal cord injury

A lysosomal marker for activated nicroglial cells involved in Alzheimer classic senile plaques

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