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

Deane, Rashid; Yan, Shi Du; Submamaryan, Ram Kumar; LaRue, Barbara; Jovanovic, Suzana; Hogg, Elizabeth; Welch, Deborah; Manness, Lawrence; Lin, Chang; Yu, Jin; Zhu, Hong; Ghiso, Jorge; Frangione, Blas; Stern, Alan; Schmidt, Ann Marie; Armstrong, Don; Arnold, Bernd; Liliensiek, Birgit; Nawroth, Peter P.; Hofman, Florence M.; Kindy, Mark S.; Stern, David M.; Zloković, Berislav V.

doi:10.1038/nm890

Cited by 1,245 publications

(1,095 citation statements)

References 45 publications

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“…However, peripheral inoculation of Aβ-containing brain extracts induces cerebral Aβ deposition in both mice and humans, suggesting that peripherally generated Aβ is able to enter the brain and participate in the pathogenesis of AD [34][35][36][37] . Receptor for advanced glycation end products (RAGE) has been suggested to transport Aβ across the BBB, from the blood into the brain 38 . Expression of the AGER gene (encoding RAGE) is upregulated in the AD brain vasculature 39,40 , indicating that influx of peripheral Aβ into the brain is increased in AD.…”

Section: Key Pointsmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Key Pointsmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…Such an upregulation of RAGE in APOE4 mice is reminiscent of what is observed in AD patients. 18 Since apoE has an important role in the clearance of Aβ 2 and RAGE is involved in the reuptake of Aβ in the brain, whereas RAGE null mice did not show any cerebral accumulation of peripheral Aβ, 16 the consequence of such combined alterations in apoE and RAGE at the BBB could result in hindered clearance of Aβ through the BBB.…”

Section: Discussionmentioning

confidence: 99%

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

Alata

Yue

St‐Amour

et al. 2014

J Cereb Blood Flow Metab

127

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Human apolipoprotein E (APOE) exists in three isoforms ε2, ε3, and ε4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood-brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [ 3 H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [ 3 H]-D-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.

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“…Conceivably, increased expression of HMGB-1 receptors after ischemia may enhance the sensitivity of brain cells to HMGB-1. To our knowledge, RAGE overexpression in ischemic brain has not yet been reported, although its role in b-amyloid metabolism and Alzheimer's disease has been studied (Deane et al, 2003;Mackic et al, 1998). Receptor for advanced glycation end product signals through pathways that involve ERK1 (extracellular Figure 7 High-mobility group box 1 upregulates the expression of inflammatory mediators in cultured glia and endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Qiu

Nakagawa

Wang

et al. 2007

J Cereb Blood Flow Metab

363

293

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The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor a (TNFa). Anti-HMGB-1 antibody suppressed TNFa upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFa and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.

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

Cited by 1,245 publications

References 45 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

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