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      RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain

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          Abstract

          Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.

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          Most cited references45

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          Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.

          A central question in Alzheimer's disease concerns the mechanism by which beta-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular beta-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as beta-amyloid levels rise, months before the appearance of beta-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal beta-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that beta-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal beta-amyloid 42 increased with aging and beta-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before beta-amyloid plaque pathology, suggesting that intracellular accumulation of beta-amyloid plays a crucial role in Alzheimer's disease.
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            TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice.

            Abnormal accumulation of the amyloid-beta peptide (Abeta) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor beta1 (TGF-beta1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Abeta deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-beta1 production in aged transgenic mice expressing the human beta-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Abeta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-beta1, Abeta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Abeta immunoreactivity associated with parenchymal plaques was inversely correlated with Abeta in blood vessels and cortical TGF-beta1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-beta1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-beta1 stimulated Abeta clearance in microglial cell cultures. These results demonstrate that TGF-beta1 is an important modifier of amyloid deposition in vivo and indicate that TGF-beta1 might promote microglial processes that inhibit the accumulation of Abeta in the brain parenchyma.
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              Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier.

              Elimination of amyloid-ss peptide (Ass) from the brain is poorly understood. After intracerebral microinjections in young mice, (125)I-Ass(1-40) was rapidly removed from the brain (t(1/2)
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                Author and article information

                Journal
                Nature Medicine
                Nat Med
                Springer Science and Business Media LLC
                1078-8956
                1546-170X
                July 2003
                June 15 2003
                July 2003
                : 9
                : 7
                : 907-913
                Article
                10.1038/nm890
                12808450
                21a12824-0fca-48a5-b938-82c1d01981c1
                © 2003

                http://www.springer.com/tdm


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