Perlecan Binds to the β‐Amyloid Proteins (Aβ) of Alzheimer's Disease, Accelerates Aβ Fibril Formation, and Maintains Aβ Fibril Stability

Castillo, Gonzalo; Ngo, Catherine; Cummings, Joel A.; Wight, Thomas N.; Snow, Alan D.

doi:10.1046/j.1471-4159.1997.69062452.x

Cited by 242 publications

(182 citation statements)

References 38 publications

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“…Vessels under 50 lm in diameter from AD patients show a decrease in the amount of collagen IV, compared with aged-matched controls (Christov et al, 2008). Heparan sulfate proteoglycans such as fibronectin and perlecan provide stability and flexibility to the basement membrane, accelerating the aggregation of Ab by high-affinity interactions (Castillo et al, 1997;Cotman et al, 2000). In AD brains, the levels of heparan sulfate proteoglycans are increased compared with agematched controls (Berzin et al, 2000;Shimizu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence suggest that biochemical and morphological alterations to basement membranes contribute to the development of CAA. In vitro incubation of Ab with laminin, collagen IV, and nidogen has been shown to prevent Ab fibrillization, whereas agrin and perlecan promote and stabilize Ab fiber formation (Castillo et al, 1997;Bronfman et al, 1998;Cotman et al, 2000;Kiuchi et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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SummaryDevelopment of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-b (Ab) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Ab contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Ab into the hippocampus or thalamus showed an agerelated reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Ab in the brain in AD and may facilitate development of improved therapeutic strategies to remove Ab from the brain in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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“…9,31 Perlecan and fibronectin have been proposed to participate in Ab accumulation by accelerating its aggregation by providing a higher stability of Ab in the basement membrane. 10,11 Interestingly, perlecan and fibronectin levels are also elevated during aging in mice, and this could in part explain the impaired drainage of Ab in the aging brain. 9,31 However, whereas perlecan is normally expressed in abundance around healthy cerebral blood vessels, it is absent around amyloid-laden blood vessels in the brains of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type patients, 33 raising the intriguing possibility that diminished perivascular perlecan expression could contribute to cerebral amyloid angiopathy.…”

Section: Discussionmentioning

confidence: 99%

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Jullienne

Roberts

Pop

et al. 2014

J Cereb Blood Flow Metab

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In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Ab) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Ab clearance. Rodent-Ab staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood-brain barrier alongside vascular dysfunction and altered Ab trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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“…Transforming growth factor mice feature increased expression of vascular growth factors (vascular endothelial growth factor; connective tissue growth factor), and accumulation of perlecan, fibronectin, laminin, and collagen in the vascular basement membrane that contribute to its thickening (WyssCoray et al, 1995(WyssCoray et al, , 2000Tong et al, 2005;Nicolakakis et al, 2011). Not only do some of these proteins have the capacity to bind Ab, and potentially initiate CAA (Castillo et al, 1997), but also their accumulation in capillary basement membranes could hinder substrate delivery and waste elimination across the blood-brain barrier. In line with this idea, TGF mice feature increased capillary basement membrane thickness and endothelial cell degeneration (Wyss-Coray et al, 2000), resting hypoperfusion throughout the brain (Gaertner et al, 2005), impaired neurovascular coupling during whisker stimulation (Nicolakakis et al, 2011) (Table 1), and reduced basal CGU (Galea et al, 2006).…”

Section: Transgenic Mouse Modelsmentioning

confidence: 99%

Neurovascular function in Alzheimer's disease patients and experimental models

Nicolakakis

Hamel

2011

J Cereb Blood Flow Metab

131

118

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The ability of the brain to locally augment glucose delivery and blood flow during neuronal activation, termed neurometabolic and neurovascular coupling, respectively, is compromised in Alzheimer's disease (AD). Since perfusion deficits may hasten clinical deterioration and have been correlated with negative treatment outcome, strategies to improve the cerebral circulation should form an integral element of AD therapeutic efforts. These efforts have yielded several experimental models, some of which constitute AD models proper, others which specifically recapture the AD cerebrovascular pathology, characterized by anatomical alterations in brain vessel structure, as well as molecular changes within vascular smooth muscle cells and endothelial cells forming the bloodbrain barrier. The following paper will present the elements of AD neurovascular dysfunction and review the in vitro and in vivo model systems that have served to deepen our understanding of it. It will also critically evaluate selected groups of compounds, the FDA-approved cholinesterase inhibitors and thiazolidinediones, for their ability to correct neurovascular dysfunction in AD patients and models. These and several others are emerging as compounds with pleiotropic actions that may positively impact dysfunctional cerebrovascular, glial, and neuronal networks in AD.

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Perlecan Binds to the β‐Amyloid Proteins (Aβ) of Alzheimer's Disease, Accelerates Aβ Fibril Formation, and Maintains Aβ Fibril Stability

Abstract: Perlecan is a specific heparan sulfate proteoglycan that accumulates in the fibrillar /3-amyloid (A~3)

Cited by 242 publications

References 38 publications

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Neurovascular function in Alzheimer's disease patients and experimental models

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