Neuroinflammation in Plaque and Vascular β-Amyloid Disorders: Clinical and Therapeutic Implications

Eikelenboom, Piet; Veerhuis, Rob; Familian, Atoosa; Hoozemans, Jeroen J. M.; Gool, Willem A. van; Rozemüller, Annemieke

doi:10.1159/000113699

Cited by 46 publications

(27 citation statements)

References 17 publications

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“…It is known that microglial activation plays a crucial role in Alzheimer's disease as microglial cells become overactivated when they are engaged in the clearance of amyloid-b (Block et al, 2007). Alternatively, amyloid-b may directly recruit and activate microglial cells as suggested by studies of congophilic angiopathy (Eikelenboom et al, 2008). Microglial activation may subsequently lead to neuronal loss and to damage in the microvasculature (Block et al, 2007).…”

Section: Qmri Increases Specificity For Neuropathological Changes Witmentioning

confidence: 99%

Heterogeneity of White Matter Hyperintensities in Alzheimer's Disease: Post-Mortem Quantitative MRI and Neuropathology

et al. 2009

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White matter hyperintensities (WMH) are frequently seen onT 2 -weighted MRI scans of elderly subjects with and without Alzheimer's disease. WMH are only weakly and inconsistently associated with cognitive decline, which may be explained by heterogeneity of the underlying neuropathological substrates. The use of quantitative MRI could increase specificity for these neuropathological changes. We assessed whether post-mortem quantitative MRI is able to reflect differences in neuropathological correlates of WMH in tissue samples obtained postmortem from Alzheimer's disease patients and from non-demented elderly. Thirty-three formalin-fixed, coronal brain slices from 11 Alzheimer's disease patients (mean age: 83 AE10 years, eight females) and 15 slices from seven non-demented controls (mean age: 78 AE10 years, four females) with WMH were scanned at 1.5 T using qualitative (fluid-attenuated inversion recovery, FLAIR) and quantitative MRI [diffusion tensor imaging (DTI) including estimation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA), and T 1 -relaxation time mapping based on flip-angle array). A total of 104 regions of interest were defined on FLAIR images in WMH and normal appearing white matter (NAWM). Neuropathological examination included (semi-)quantitative assessment of axonal density (Bodian), myelin density (LFB), astrogliosis (GFAP) and microglial activation (HLA-DR). Patient groups (Alzheimer's disease versus controls) and tissue types (WMH versus NAWM) were compared with respect to QMRI and neuropathological measures. Overall, Alzheimer's disease patients had significantly lower FA (P _ 0.01) and higher T 1 -values than controls (P = 0.04). WMH showed lower FA (P _ 0.01) and higher T 1 -values (P _ 0.001) than NAWM in both patient groups. A significant interaction between patient group and tissue type was found for the T 1 measurements, indicating that the difference inT 1 -relaxation time between NAWM and WMH was larger in Alzheimer's disease patients than in non-demented controls. All neuropathological measures showed differences between WMH and NAWM, although the difference in microglial activation was specific for Alzheimer's disease. Multivariate regression models revealed that in Alzheimer's disease, axonal density was an independent determinant of FA, whereas T 1 was independently determined by axonal and myelin density and microglial activation. Quantitative MRI techniques reveal differences in WMH between Alzheimer's disease and non-demented elderly, and are able to reflect the severity of the neuropathological changes involved.Keywords: age-related white matter hyperintensities; post-mortem MRI; Alzheimer's disease; neuropathological characteristics Abbreviations: 3D-FLAIR = 3D-fluid-attenuated inversion recovery; ADC = apparent diffusion coefficient; CERAD = Consortium to establish a Registry for Alzheimer's disease; DTI = diffusion tensor imaging; FA = fractional anisotropy; FLASH = fast low-angle shot; GFAP = glial fibrillary acidic protein; HE = haematoxylin^eosin; L...

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Section: Qmri Increases Specificity For Neuropathological Changes Witmentioning

confidence: 99%

Heterogeneity of White Matter Hyperintensities in Alzheimer's Disease: Post-Mortem Quantitative MRI and Neuropathology

et al. 2009

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“…With the realization that oligomers, rather than fibrils, likely were the primary culprits, the focus shifted towards reducing the steady-state concentration of the toxic oligomers [7][8][9]. However, the therapeutic applicability of this approach is questionable because amyloid deposits may be toxic themselves, the very process of their growth may contribute to cytotoxicity and tissue damage [10], and accelerating fibril formation may induce a harmful pro-inflammatory response [11].…”

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confidence: 99%

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Attar

Rahimi

Bitan

2013

Translational Neuroscience

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Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no diseasemodifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies -the green-tea derivative (-)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01's effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.

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“…Activated microglia are found in the vicinity of compact plaques in the brains of AD patients and in transgenic AD mouse models [38]. The other plaque prototype, i.e.…”

Section: Microglia and Amyloid Plaquesmentioning

confidence: 99%

Microglial Activation in Alzheimers Disease

Schlachetzki¹,

Hüll²

2009

CAR

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Alzheimer's disease (AD) is a devastating chronic neurodegenerative disease with currently no available disease modifying treatment. In recent years, the peptide amyloid-beta has been proposed as the major pathogenic force in the development and progression of AD. Microglia, the resident immune and phagocytic cells of the brain, are known to constantly scan brain tissue and to respond to various pathological stimuli. Thus, newly formed plaque composed of A beta seem to activate and recruit microglia in AD transgenic mice. However, the role of microglia is only poorly understood in AD. Microglia may act as a double-edged sword being either detrimental or protective depending on the context. In this mini-review, we discuss the importance of microglia and its receptors in neuroinflammation and plaque clearance. A possible disease modifying role of blood-borne monocytes, which are close relatives of bone-marrow derived microglia, will also be addressed.

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Neuroinflammation in Plaque and Vascular β-Amyloid Disorders: Clinical and Therapeutic Implications

Cited by 46 publications

References 17 publications

Heterogeneity of White Matter Hyperintensities in Alzheimer's Disease: Post-Mortem Quantitative MRI and Neuropathology

Heterogeneity of White Matter Hyperintensities in Alzheimer's Disease: Post-Mortem Quantitative MRI and Neuropathology

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Microglial Activation in Alzheimers Disease

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