Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer.

Mačkić, Jasmina B.; Stins, Monique F.; McComb, J. Gordon; Calero, Miguel; Ghiso, Jorge; Kim, K. S.; Yan, Shirley ShiDu; Stern, David M.; Schmidt, Ann Marie; Frangione, Blas; Zloković, Berislav V.

doi:10.1172/jci2029

Cited by 231 publications

(174 citation statements)

References 48 publications

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“…• An imbalance between the production and clearance of amyloid-β (Aβ) is an early, often initiating, factor in Alzheimer disease (AD) • Peripheral systems are suggested to be involved in Aβ production and clearance • The central and peripheral pathways of Aβ metabolism communicate with each other, and work synergistically to clear Aβ from the brain • Increasing experimental, epidemiologic and clinical evidence suggests that AD manifestations extend beyond the brain, and that AD pathogenesis is closely associated with systemic abnormalities • The systemic abnormalities in patients with AD might not be secondary to the cerebral degeneration; instead, they might reflect underlying disease processes • A systemic view of AD provides a novel perspective for understanding the role of Aβ in AD pathogenesis and offers opportunities for the development of new treatments and diagnostic biomarkers for AD 29 . The arachnoid villi absorb Aβ in the CSF and mediate its release into the circulation 30 .…”

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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“…75 These studies were expanded to demonstrate that RAGE was responsible for the influx of Ab across BBB. 76,77 Interaction of Ab and RAGE at the endothelial surface was shown to induce the production of pro-inflammatory cytokines and endothelin-1, a potent vasoconstrictor, thus reducing cerebral blood flow and potentially exacerbating AD pathology. 76 RAGE is implicated in AD pathogenesis not only through mediation of Ab influx across BBB, but also through inflammatory and pro-coagulant activity within the endothelium, production of reactive oxygen species and the induction of apoptosis through the nuclear factor-êB pathway.…”

Section: Influx Of Ab Rage/ab Interactions At Bbbmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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“…Although it is not yet clear which species of Aβ (soluble or insoluble) binds to RAGE (Yan et al ., 2009), the strong increase of RAGE in the high‐AGE diet group together with the significant correlation of insoluble Aβ 42 with AGEs intake suggests that insoluble Aβ binds to RAGE. This is consistent with the influx of Aβ across the BBB depending on its interaction with RAGE (Mackic et al ., 1998) and that it was shown that AGEs increase the amount of fibronectin in pericytes and directly induce hypertrophy at the BBB via RAGE signaling (Shimizu et al ., 2013). In addition, levels of AGEs were significantly higher (~twofold) in hippocampal insoluble Aβ fraction in the Tg2576 group on H‐AGE diet compared to the other three groups as shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

et al. 2016

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SummaryThere is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD‐like model mice on high‐AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle‐linked disease epidemic.

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Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer.

Abstract: Abstract

Cited by 231 publications

References 48 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

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

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