Aβ peptides can enter the brain through a defective blood–brain barrier and bind selectively to neurons

Clifford, Peter; Zarrabi, Shabnam; Siu, Gilbert; Kinsler, Kristin; Kosciuk, Mary C.; Venkataraman, V.; D’Andrea, Michael R.; Dinsmore, Steven; Nagele, Robert G.

doi:10.1016/j.brainres.2007.01.070

Cited by 120 publications

(134 citation statements)

References 81 publications

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“…In addition to A␤ being produced intracellularly, previously secreted A␤ that forms an extracellular A␤ pool can be taken up by cells and internalized into intracellular pools through various receptors and trasnporters. A recent study showed that, in mice with a toxin-induced compromise of the blood-brain barrier, fluorescently labeled A␤ that is injected into the tail vein can accumulate intracellularly in pyramidal neurons in the cerebral cortex [110]. The results presented by the authors provide direct evidence that neurons can take up extracellular A␤, one of mechanisms that has been proposed is the endocytocis of A␤ oligomers [111].…”

Section: Intracellular A␤ Oligomer Toxicitymentioning

confidence: 86%

Molecular Mechanisms of Amyloid Oligomers Toxicity

Kayed

Lasagna‐Reeves

2012

JAD

326

283

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Abstract. Amyloid oligomers have emerged as the most toxic species of amyloid-␤ (A␤). This hypothesis might explain the lack of correlation between amyloid plaques and memory impairment or cellular dysfunction. However, despite the numerous published research articles supporting the critical role A␤ oligomers in synaptic dysfunction and cell death, the exact definition and mechanism of amyloid oligomers formation and toxicity still elusive. Here we review the evidence supporting the many molecular mechanisms proposed for amyloid oligomers toxicity and suggest that the complexity and dynamic nature of amyloid oligomers may be responsible for the discrepancy among these mechanisms and the proposed cellular targets for amyloid oligomers.

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Section: Intracellular A␤ Oligomer Toxicitymentioning

confidence: 86%

Molecular Mechanisms of Amyloid Oligomers Toxicity

Kayed

Lasagna‐Reeves

2012

JAD

326

283

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“…3 and supplemental Figs. S3-S6) demonstrate that exogenous aggregated A␤(1-42) is capable of entering the cells through an endocytotic lysosomal pathway (67,70,93,94) or a non-endocytotic pathway (95). After the initial uptake of A␤, the A␤ peptides can accumulate in the cytosol, peroxisomes, mitochondria, and other intracellular compartments.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Habib

Lee

Yang

2010

Journal of Biological Chemistry

102

120

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Although oxidative stress is commonly associated with aging (1, 2), patients with Alzheimer disease (AD) 3 often exhibit increased oxidative damage (3-10) and subsequent neuronal loss in ␤-amyloid (A␤)-rich regions of the brain. The molecular mechanisms by which A␤ contributes to oxidative damage remain unclear (11)(12)(13)(14)(15)(16)(17)(18)(19). Understanding these mechanisms, however, is critical for developing effective methods to manage the disease. One mechanism for A␤-induced cellular oxidative stress proposes that A␤ peptides interact directly with cellular enzymes responsible for maintaining low physiological levels of reactive oxygen species (ROS) (20 -23). Two potential outcomes from such pathological protein-amyloid interactions are: 1) increased production of ROS, or 2) reduced degradation of ROS.The major ROS in cells are superoxide and the more reactive hydrogen peroxide (H 2 O 2 )-derived hydroxyl radical (24, 25). Both superoxide and H 2 O 2 are primarily produced in the mitochondria (26 -28). A␤ peptides have been shown to accumulate in the mitochondria (29, 30), and, therefore, could exert their detrimental effects through interaction with mitochondrial proteins (23, 31-34). Superoxide is produced by several enzymecatalyzed reactions in the mitochondria (25). Behl et al. (11) however, showed that a broad range of inhibitors of several of these enzymes had no effect on 〈␤ toxicity in clonal and primary neuronal cell cultures. Furthermore, Zhang et al. (35) reported that superoxide levels in cells were not substantially elevated upon exposure to 〈␤. These findings suggest that superoxide is not a dominant contributor to 〈␤ toxicity.On the other hand, 〈␤-induced cellular increase in H 2 O 2 or its metabolites is strongly correlated with 〈␤ toxicity (11, 13, 36). H 2 O 2 can be generated by several mitochondrial enzymes including monoamine oxidases, superoxide dismutase, and xanthine oxidase (25). Behl et al. (11) showed that inhibitors of monoamine oxidases and xanthine oxidase had no effect on 〈␤-induced H 2 O 2 accumulation or 〈␤ toxicity. Gsell et al. (37) also found that the activity of superoxide dismutase was unaltered in the brains of AD patients. Additionally, Rensink et al. (38) reported that the Dutch mutation of 〈␤ peptides (HCHWA-D 〈␤) did not bind directly to superoxide dismutase and Kaminsky et al. (39) reported only a relatively small effect of 〈␤ on superoxide dismutase activity and H 2 O 2 production upon chronic exposure of rat brains to 〈␤. These results suggest that 〈␤ peptides do not significantly affect production of H 2 O 2 in cells. Consequently, these findings imply that 〈␤-induced oxidative stress may arise from reduced degradation of H 2 O 2 in 〈␤-challenged cells.Degradation of H 2 O 2 in cells is primarily achieved by the enzymes catalase and glutathione peroxidase (GPx), both inside and outside of the mitochondria (25). Sagara et al. (40) found that cells resistant to 〈␤ toxicity had elevated levels of catalase and GPx. The activity of both enzymes was redu...

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“…Clifford et al [66] Alzheimer's disease Autopsy tissue histochemistry Ab42, complement and IgG were all found to leak from arterioles in brains from AD patients.…”

Section: Blood-brain Barriersmentioning

confidence: 99%

“…Clifford et al [66] Alzeimer's disease Toxin-induced BBB permeability Histochemistry Ab40 and Ab42 entered the brain through disrupted BBB and bound to nearby neurones, but only to specific neuronal subtypes.…”

Section: Tg-swdi Mousementioning

confidence: 99%

Review: Role of developmental inflammation and blood–brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases

Stolp

Dziegielewska

2009

Neuropathology Appl Neurobio

220

161

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The causes of most neurological disorders are not fully understood. Inflammation and blood–brain barrier dysfunction appear to play major roles in the pathology of these diseases. Inflammatory insults that occur during brain development may have widespread effects later in life for a spectrum of neurological disorders. In this review, a new hypothesis suggesting a mechanistic link between inflammation and blood–brain barrier function (integrity), which is universally important in both neurodevelopmental and neurodegerative diseases, is proposed. The role of inflammation and the blood–brain barrier will be discussed in cerebral palsy, schizophrenia, Parkinson's disease, Alzheimer's disease and multiple sclerosis, conditions where both inflammation and blood–brain barrier dysfunction occur either during initiation and/or progression of the disease. We suggest that breakdown of normal blood–brain barrier function resulting in a short‐lasting influx of blood‐born molecules, in particular plasma proteins, may cause local damage, such as reduction of brain white matter observed in some newborn babies, but may also be the mechanism behind some neurodegenerative diseases related to underlying brain damage and long‐term changes in barrier properties.

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Aβ peptides can enter the brain through a defective blood–brain barrier and bind selectively to neurons

Cited by 120 publications

References 81 publications

Molecular Mechanisms of Amyloid Oligomers Toxicity

Molecular Mechanisms of Amyloid Oligomers Toxicity

Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Review: Role of developmental inflammation and blood–brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases

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