The innate immune response and inflammatory signaling play determinant roles in brain homeostasis, neuroprotection, and repair; however, altered or excessive signaling in these injury defense systems contributes to the irreversible degeneration of brain cells, as typified in the common, age-related neurodegenerative disorder Alzheimer disease (AD). Abundant DNA array, Northern, RT-PCR, and Western gene expression analysis of AD brains have repeatedly shown a significant disruption in the homeostatic expression of essential brain genes and a progressive up-regulation of inflammatory gene expression, driven in part by overactivation of transcription factor NF-B. This supports both the development and progression of neurodegenerative disease processes (9 -16). Indeed the TLR/IL-1R-IRAK-NF-B signaling axis is substantially over-stimulated in AD brain (6, 9 -12). Components of this innate immunity and inflammatory pathway are known to play a central role in driving neuropathology, in part via overexpression of interleukin-1 ␤ (IL-1␤) and upregulating the generation of the 42-amino acid amyloid ␤ 42 (A␤42) peptide. These in turn induce transcription from the * This work was supported, in whole or in part, by National Institutes of Health Grant AG18031 (NIA; to W. J. L.

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Micro RNA-146a (miRNA-146a) is an inducible, 22 nucleotide, small RNA over-expressed in Alzheimer’s disease (AD) brain. Up-regulated miRNA-146a targets several inflammation-related and membrane-associated messenger RNAs (mRNAs), including those encoding complement factor-H (CFH) and the interleukin-1 receptor associated kinase-1 (IRAK-1), resulting in significant decreases in their expression (p < 0.05, ANOVA). In this study we assayed miRNA-146a, CFH, IRAK-1 and tetraspanin-12 (TSPAN12), abundances in primary human neuronal-glial (HNG) co-cultures, in human astroglial (HAG) and microglial (HMG) cells stressed with Aβ42 peptide and tumor necrosis factor alpha (TNFα). The results indicate a consistent inverse relationship between miRNA-146a and CFH, IRAK-1 and TSPAN12 expression levels, and indicate that HNG, HAG and HMG cell types each respond differently to Aβ42-peptide + TNFα-triggered stress. While the strongest miRNA-146a-IRAK-1 response was found in HAG cells, the largest miRNA-146a-TSPAN12 response was found in HNG cells, and the most significant miRNA-146a-CFH changes were found in HMG cells, the ‘resident scavenging macrophages’ of the brain.

Murine transgenic models of Alzheimer’s disease (Tg-AD) have been useful to analyze the contribution of β-amyloid precursor protein (βAPP), Aβ42 peptide deposition, and the proinflammatory mechanisms that characterize Alzheimer-type neuropathology. In this report, we have studied the levels of βAPP, Aβ40 and Aβ42 peptide, as well as the innate immune and inflammatory response-regulator complement factor H in the brain and retina in four different Tg-AD models including Tg2576, PSAPP, 3xTg-AD, and 5xFAD. Aged, symptomatic 5xFAD mice showed the highest retinal abundance of Aβ42 peptides and the highest deficits in complement factor H. This may be a useful model to study the mechanisms of amyloidmediated inflammatory degeneration. The superior colliculus and retina obtained from late-stage Alzheimer’s disease revealed upregulated amyloidogenic and inflammatory signaling along the anteroposterior axis of the retinal-primary visual cortex pathway.