Vascular disorder in Alzheimer’s disease: role in pathogenesis of dementia and therapeutic targets

Zloković, Berislav V.

doi:10.1016/s0169-409x(02)00150-3

Cited by 61 publications

(49 citation statements)

References 56 publications

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“…Freshly solubilized A␤42, contrary to A␤40, eluted from the Superdex 75 column in two well defined peaks at 8 and 15 min, with the front peak (fraction 42 8 ) accountable for almost half of the total peptide loaded onto the column. Fraction 42 15 eluted with the same retention time as its A␤40 counterpart (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The blood-brain barrier has the capability to modulate sA␤ brain uptake and clearance by controlling the uptake of circulating sA␤, either in its free form or bound to its transport apolipoproteins, as well as the elimination of brain-derived A␤ via transport-mediated clearance mechanisms (reviewed in Ref. 8). Experimentally determined transport rates indicate that the receptor for advance glycation end products mediates the influx of free A␤ into the brain (9), whereas low density lipoprotein receptor-related protein 2 (LRP-2, also known as gp330 or megalin) is the receptor involved in the uptake of A␤-apoJ complexes (10).…”

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confidence: 99%

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Systemic Catabolism of Alzheimer's Aβ40 and Aβ42

Ghiso

Shayo²,

Calero

et al. 2004

Journal of Biological Chemistry

170

137

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To better understand the physiologic excretion and/or catabolism of circulating peripheral amyloid ␤ (A␤), we labeled human A␤40 (monomeric, with predominant unordered structure) and A␤42 (mixture of monomers and oligomers in ϳ50:50 ratio, rich in ␤-sheet conformation) with either Na 125 I or 125 I-tyramine cellobiose, also known as the cell-trapping ligand procedure, testing their blood clearance and organ uptake in B6SJLF1/J mice. Irrespective of the labeling protocol, the peptide conformation, and the degree of oligomerization, both A␤40 and A␤42 showed a short half-life of 2.5-3.0 min. The liver was the major organ responsible for plasma clearance, accounting for >60% of the peptide uptake, followed by the kidney. In vivo, hepatocytes captured >90% of the radiolabeled peptides which, after endocytosis, were preferentially catabolized and excreted into the bile. Biliary excretion of intact as well as partially degraded A␤ species became obviously relevant at doses above 10 g. The use of biotin-labeled A␤ allowed the visualization of the interaction with HepG2 cells in culture, whereas competitive inhibition experiments with unlabeled A␤ demonstrated the specificity of the binding. The capability of the liver to uptake, catabolize, and excrete large doses of A␤, several orders of magnitude above its physiologic concentration, may explain not only the femtomolar plasma levels of A␤ but the little fluctuation observed with age and disease stages. Alzheimer's disease (AD)1 is the most frequent type of amyloidosis in humans and the commonest form of clinical dementia. Extracellular A␤ amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy as well as intraneuronal neurofibrillary tangles co-exist in the brain parenchyma, being the cognitive areas the most severely affected. A␤, a 39 -42-amino acid-long peptide of unknown biological function, is an internal processing product of a larger type I transmembrane precursor molecule, APP, codified by a single multiexonic gene located on chromosome 21 (reviewed in Ref. 1). A soluble form of A␤ (sA␤) is present in the biological fluids of both normal individuals and AD patients as well as in cytosolic soluble fractions of normal, AD, and Down's syndrome brain homogenates (2-6). Notably, an increased amount of sA␤ has been reported in AD and Down's syndrome brain tissue in comparison to control individuals (7). Although the primary structures of deposited A␤ and sA␤ are indistinguishable, the circulating peptide is predominantly 40 residues long, whereas sA␤42, the major species in parenchymal deposits, is only a minor component of the circulating pool. To the present, it is not clear whether circulating sA␤s reflect systemic production, brain clearance, or both. The blood-brain barrier has the capability to modulate sA␤ brain uptake and clearance by controlling the uptake of circulating sA␤, either in its free form or bound to its transport apolipoproteins, as well as the elimination of brain-derived A␤ via transport-mediated clearance mechanisms (r...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Systemic Catabolism of Alzheimer's Aβ40 and Aβ42

Ghiso

Shayo²,

Calero

et al. 2004

Journal of Biological Chemistry

170

137

View full text Add to dashboard Cite

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“…Disruption of the BBB after insults to the CNS such as trauma and stroke or neurodegenerative conditions such as Alzheimer's disease is beginning to be an area of intensive research (Petty and Lo, 2002;Zlokovic, 2002). This attention is attributable to the recent appreciation that neuronal function is intimately linked to vascular function, acting together to control brain function and pathology.…”

Section: Discussionmentioning

confidence: 99%

Enhancing Expression of Nrf2-Driven Genes Protects the Blood–Brain Barrier after Brain Injury

Zhao¹,

Moore²,

Redell³

et al. 2007

J. Neurosci.

247

204

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The integrity of the blood-brain barrier (BBB) is critical for normal brain function, and its compromise contributes to the pathophysiology of a number of CNS diseases and injuries. Using a rodent model of brain injury, the present study examines the pathophysiology of BBB disruption. Western blot and immunohistochemical analyses indicate that brain injury causes a loss of capillary endothelial cells and tight junction proteins, two critical components of the BBB. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) by sulforaphane, a naturally occurring compound present in high levels in cruciferous vegetables, significantly increased the expression of endogenous cytoprotective genes in brain tissue and microvessels as indicated by real-time PCR analysis. Postinjury administration of sulforaphane reduced the loss of endothelial cell markers and tight junction proteins and preserved BBB function. These protective effects were dependent on the activity of Nrf2. Injured rats pretreated with decoy oligonucleotides containing the binding site of Nrf2, and mice lacking the nrf2 gene, did not benefit from sulforaphane administration. These findings indicate a potential therapeutic usefulness for Nrf2-activating molecules to improve the function of the neurovascular unit after injury.

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“…16 Specific attention has recently focused on changes within brain endothelial cells in AD and in response to exposure to Aβ. 16 It has been hypothesized that during the onset of AD the breakdown of the blood-brain barrier results in an neuroinflammatory response leading to increased transport of soluble Aβ across the endothelium, 17,18 the upregulation of inflammatory adhesion molecule expression in response to nuclear factor κB, and subsequent infiltration of inflammatory leukocytes into the brain. 19 This hypothesis has been supported by data showing that Aβ exposure of the basal compartment of endothelial monolayers in culture results in increased monocyte transendothelial migration.…”

Section: Evidence From Experimental Studiesmentioning

confidence: 99%

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

Thiel

Cechetto

Heiss

et al. 2014

Stroke

109

102

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O ne in 5 patients with stroke will end up demented shortly after a stroke, half with prior cognitive impairment and half without. After recurrent stroke, more than a third will become demented. 1 The mechanisms remain unclear beyond the fact that neurodegenerative and vascular mechanisms contribute to the cognitive decline.2 In this review, we explore experimental and clinical evidence of interaction between ischemia, amyloid deposition, and neuroinflammation and identify new potential therapeutic targets. Evidence From Experimental StudiesClinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated dementia, 3 and experimental studies with animals have addressed the relationship between stroke and AD. [4][5][6][7][8][9] Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ 1-42 ) accumulate in patients with multi-infarct dementia, 10,11 there are animal studies examining neurodegenerative mechanisms and cognitive impairment in global and focal experimental ischemia. Changes in neurotransmitter systems, trophic factors, and cell signaling and neuroinflammatory mechanisms have been well documented.12 Experimental animal models of cognitive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage.13 Studies in mice overexpressing mutated presenilin 1 or presenilinknockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotoxicity. 9,14 This may suggest that mutations leading to higher levels of Aβ may increase the sensitivity to ischemia. In another study, mice overexpressing amyloid precursor protein with middle cerebral artery occlusion were shown to have enlarged infarcts and a stronger reduction of blood flow after the arterial occlusion.15 These experiments, however, also showed that the vasodilatory effect of the endothelium-dependent vasodilator acetylcholine was significantly reduced in transgenic mice, possibly suggesting that Aβ-induced disturbance in endothelium-dependent vascular reactivity may contribute to the higher ischemia sensitivity. Our research group has conducted several studies directly examining the pathological, neuroinflammatory, and behavioral relationship of stroke and AD in rat and mouse models. [4][5][6][7] In particular, these studies have focused on the potential synergism that would account for the clinical findings. A consequence of a chronic neuroinflammatory response is perturbation of the cerebrovascular system. Likewise, a perturbation of the cerebrovascular system will influence the degree of neuroinflammation after injury. A considerable body of evidence has demonstrated that AD is directly related to and has profound pathological changes in the cerebral microvasculature.16 Specific attention has recently focused on changes within brain endothelial cells in AD and in response to exposure to Aβ. 16 It has been hypothesized that during the onset of AD the breakdow...

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Vascular disorder in Alzheimer’s disease: role in pathogenesis of dementia and therapeutic targets

Cited by 61 publications

References 56 publications

Systemic Catabolism of Alzheimer's Aβ40 and Aβ42

Systemic Catabolism of Alzheimer's Aβ40 and Aβ42

Enhancing Expression of Nrf2-Driven Genes Protects the Blood–Brain Barrier after Brain Injury

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

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