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Review
. 2009;16(4):833-43.
doi: 10.3233/JAD-2009-1030.

RAGE and Alzheimer's Disease: A Progression Factor for Amyloid-Beta-Induced Cellular Perturbation?

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Free PMC article
Review

RAGE and Alzheimer's Disease: A Progression Factor for Amyloid-Beta-Induced Cellular Perturbation?

Shi Du Yan et al. J Alzheimers Dis. .
Free PMC article

Abstract

Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-beta peptide (Abeta) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Abeta-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Abeta-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Abeta-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-beta protein precursor. Interception of Abeta interaction with RAGE, by infusion of soluble RAGE, decreases Abeta content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Abeta accumulation. These data suggest that RAGE may be a therapeutic target for AD.

Figures

Fig. 1
Fig. 1
Administration of sRAGE to mice bearing a mutant human AβPP transgene (Tg PD-hAPP mice) reduces cerebral amyloidosis. Total Aβ (panel a) and Aβ1–42 (panel b) were determined by ELISA in nontransgenic (negative for the transgene) or transgenic PD-hAPP mice (+ for the transgene) who were administered sRAGE (or vehicle) from the ages of 6–9 months, as indicated. In panel c, image analysis of amyloid load from the experiments in panels a-b is shown. Adapted from Deane et al. [47].
Fig. 2
Fig. 2
Cerebral blood flow, Aβ, and RAGE. a) Cerebral blood flow (CBF) and systemic blood pressure (BP) are shown after infusion of human Aβ1–40 at the indicated time, b) Regional CBF after administration of vehicle (red), Aβ1–40 (orange), Aβ1–40+ anti-RAGE IgG (yellow); Aβ1–40+ nonimmune IgG (green) was determined in the motor cortex (MOT), sensory cortex (SEN), striatum (STR), callosum (CALL) and thalamus (THAL). Adapted from Deane et al. [47]. (Colours are visible in the electronic version of the article at www.iospress.nl)
Fig. 3
Fig. 3
Increased cerebral blood flow in 9 month old Tg2576 mice treated anti-RAGE IgG (α-RAGE), sRAGE but not nonimmune (NI) IgG. Adapted from Deane et al. [47].
Fig. 4
Fig. 4
Nuclear extracts from cerebral cortex of 3–4-month old double transgenic mice bearing a transgene driving overexpression of neuronal RAGE and a transgene expressing mutant human amyloid precursor protein were studied by electrophoretic mobility shift assay using a consensus NF-κB probe. A1) RAGE indicates the presence (+) or absence (−) of the RAGE transgene. mAPP indicates the presence (+) or absence (−) of the mutant amyloid precursor protein transgene. A2) The same experiment as in panel A1 was conducted, but certain double transgenics had the wild-type RAGE transgene replaced by a transgene encoding dominant negative (DN) RAGE. The presence (+) or absence (−) of the DN-RAGE transgene is indicated. Adapted from Arancio et al. [54]
Fig. 5
Fig. 5
Analysis of spatial learning and memory in double transgenic mice (Tg RAGE/mAPP) using the radial arm water maze at 3–4 (A) and 5–6 (B) months of age. Symbols denote: RAGE, mice expressing the RAGE transgene only; APP, mice expressing the mutant AβPP transgene only; nonTg, nontransgenic age- and strain-matched littermates; and APP/RAGE, double transgenic mice expressing the mutant AβPP and RAGE transgenes. Adapted from Arancio et al. [54].
Fig. 6
Fig. 6
Effect of RAGE on Aβ1–42 (200 nM)-induced inhibition of LTP in slices of entorhinal cortex. Exposure to Aβ (dark bar) did not prevent development of LTP in samples derived from homozygous RAGE null mice or in slices from wild-type mice preincubated with blocking antibody to RAGE. Vehicle-treated slices from wild-type mice exposed to Aβ are shown in grey. HFS = high frequency stimulation protocol used to induce LTP in cortical slices. Adapted from Origlia [64].

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