Early changes in extracellular matrix in Alzheimer's disease

Lepelletier, François‐Xavier; Mann, David; Robinson, Andrew C; Pinteaux, Emmanuel; Boutin, Hervé

doi:10.1111/nan.12295

Cited by 152 publications

(158 citation statements)

References 77 publications

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“…Kalaria and Hedera (1995) have shown loss of staining of the endothelial markers CD31 and CD34 in capillaries but retained basement membrane COL4 immunoreactivity in AD brains. However, other studies have demonstrated no difference in CD31 staining between moderate-to-severe AD, subclinical AD, and control patients in frontal and temporal cortices (Lepelletier et al, 2017). Zhang et al (1998) found no difference in endothelial markers in brains with severe arterial and arteriolar CAA, with or without AD, compared with controls.…”

Section: Discussionmentioning

confidence: 97%

“…Thickening of the capillary basement membrane with increase in collagen content, which could disrupt transport into and out of the brain, has also been reported in the brains of subjects with AD and Parkinson disease (Farkas et al, 2000; Kalaria and Pax, 1995; Tian et al, 2006). Furthermore, these vascular changes appear to occur early in the course of disease as COL4, perlecan, and fibronectin, components of the perivascular extracellular matrix, were increased in both subclinical AD subjects and AD patients compared with controls, without a further increase in AD patients compared with those with subclinical AD (Lepelletier et al, 2017). However, other studies have shown no difference in the collagen content in the cerebral vasculature.…”

Section: Discussionmentioning

confidence: 99%

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The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier

Magaki

Tang

Tung

et al. 2018

Neurobiology of Aging

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Cerebral amyloid angiopathy (CAA), in which amyloid accumulates predominantly in the walls of arterioles and capillaries, is seen in most patients with Alzheimer disease (AD) and may contribute to compromise of blood-brain barrier (BBB) function seen in AD. We investigated the effects of CAA on BBB integrity by examining the expression of the endothelial marker CD31, basement membrane protein collagen IV (COL4), tight junction protein claudin-5, and fibrinogen, a marker of BBB leakage, by immunohistochemistry in the occipital cortex of autopsy brains with AD and capillary CAA (CAA type 1; n = 8), AD with noncapillary CAA (CAA type 2; n = 10), and AD without CAA (n = 7) compared with elderly controls (n = 10). Given the difference in pathogenesis of capillary and noncapillary CAA, we hypothesize that features of BBB breakdown are observed only in capillary CAA. We found decreased expression of CD31 in AD subjects with CAA types 1 and 2 compared with AD without CAA and an increase in COL4 in AD without CAA compared with controls. Furthermore, there was increased immunoreactivity for fibrinogen in AD with CAA type 1 compared with controls. These findings suggest that capillary CAA is associated with morphologic and possibly physiologic alterations of the neurovascular unit and increased BBB permeability in AD.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier

Magaki

Tang

Tung

et al. 2018

Neurobiology of Aging

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“…Additionally, fibronectin triggers the activation of microglia in vitro (33), and thus may stimulate macrophage/microglial activation in RIBI. Fibronectin is also increased in the cortex (34) and plasma (35) of humans with clinical and subclinical Alzheimer’s disease. The cortical deposition of fibronectin may play a role in the pathology of cognitive dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

et al. 2017

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Andrews, R. N., Metheny-Barlow, L. J., Peiffer, A. M., Hanbury, D. B., Tooze, J. A., Bourland, J. D., Hampson, R. E., Deadwyler, S. A. and Cline, J. M. Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates. Radiat. Res. 187, 599–611 (2017). Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6–11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and vascular endothelial growth factor beta (VEGFB) mRNAs were increased within temporal white matter. We also demonstrate that radiation-induced brain injury is associated with decreases in white matter-specific expression of neurotransmitter receptors SYP, GRIN2A and GRIA4. We additionally provide evidence that macrophage/microglial mediated neuroinflammation may contribute to RIBI through increased gene expression of the macrophage chemoattractant CCL2 and macrophage/ microglia associated CD68. Global patterns in cerebral gene expression varied significantly between regions examined (P < 0.0001, Friedman’s test), with effects most prominent within cerebral white matter.

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“…Alterations to extracellular matrix (ECM) stiffness and density occur during tissue aging [1] and disease [2–5] and have the potential to impact cell behavior within the tissue. For example, numerous in vitro studies have shown that substrate rigidity can influence the organization and generation of intracellular forces [6], overall cell morphology [7, 8], and intracellular signaling [9, 10], thereby affecting the differentiation of stem cells [11], migration of a variety of cell types [12–14], and invasiveness of cancer cells [15].…”

Section: Introductionmentioning

confidence: 99%

Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen

et al. 2017

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The extracellular microenvironment provides critical cues that guide tissue development, homeostasis, and pathology. Deciphering the individual roles of these cues in tissue function necessitates the development of physically tunable culture platforms, but current approaches to create such materials have produced scaffolds that either exhibit a limited mechanical range or are unable to recapitulate the fibrous nature of in vivo tissues. Here we report a novel interpenetrating network (IPN) of gelatin-methacrylate (gelMA) and collagen I that enables independent tuning of fiber density and scaffold stiffness across a physiologically-relevant range of shear moduli (2–12 kPa), while maintaining constant extracellular matrix content. This biomaterial system was applied to examine how changes in the physical microenvironment affect cell types associated with the tumor microenvironment. By increasing fiber density while maintaining constant stiffness, we found that MDA-MB-231 breast tumor cells required the presence of fibers to invade the surrounding matrix, while endothelial cells (ECs) did not. Meanwhile, increasing IPN stiffness independently of fiber content yielded decreased invasion and sprouting for both MDA-MB-231 cells and ECs. These results highlight the importance of decoupling features of the microenvironment to uncover their individual effects on cell behavior, in addition to demonstrating that individual cell types within a tissue may be differentially affected by the same changes in physical features. The mechanical range and fibrous nature of this tunable biomaterial platform enable mimicry of a wide variety of tissues, and may yield more precise identification of targets which may be exploited to develop interventions to control tissue function.

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Early changes in extracellular matrix in Alzheimer's disease

Abstract: Present data support the hypothesis that significant ECM changes occur during the early stages of AD. ECM changes affecting brain microvascular functions could therefore drive disease progression and provide potential new early investigational biomarkers in AD.

Cited by 152 publications

References 77 publications

The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier

The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen

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