Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease

Kisilevsky, Robert; Lemieux, Laura J.; Fraser, Paul E.; Kong, Xianqi; Hultin, Philip G.; Szarek, Walter A.

doi:10.1038/nm0295-143

Cited by 351 publications

(230 citation statements)

References 26 publications

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“…Tomiyama et al (1996) suggested that Rif binds to Aß by hydrophobic interactions between its lipophilic ansa chain and the hydrophobic region of Aß, thus blocking associations between Aß molecules leading to fAß formation. The anti-amyloidogenic and fibril-destabilizing activity of tetracycline (Tc), small-molecule anionic sulphonates or sulphates, melatonin, ß-sheet breaker peptides (iAß5) and nicotine may also be related to the propensity to bind to the specific sites of Aß (Kisilevsky et al 1995;Soto et al 1996;Pappolla et al 1998;Forloni et al 2001;Zeng et al 2001). Thus, it may be reasonable to consider that NSAIDs could exhibit their anti-amyloidogenic and fibril-destabilizing effects by directly binding to Aßs and/or fAßs.…”

Section: Discussionmentioning

confidence: 99%

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid ß-peptides (Aß) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term uses of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of developing AD and delay the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of ß-amyloid fibrils (fAß) at pH 7.5 at 37˚C in vitro. All examined NSAIDs dose-dependently inhibited formation of fAß from fresh Aß(1-40) and Aß(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fAßs. The overall activity of the molecules examined was in the following order: ibuprofen ≈ sulindac sulfide ≥ meclofenamic acid sodium salt > aspirin ≈ ketoprofen ≥ flurbiprofen ≈ diclofenac sodium salt > naproxen ≈ indomethacin. Although the mechanisms by which these NSAIDs inhibit fAß formation from Aß, and destabilize preformed fAß in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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“…4). The studies by Snow et al (1) would suggest that complexes formed between A␤-containing peptides and short HS chains do not lead to amyloid deposits, and others have reported that small polysulfated molecules can displace HS glycosaminoglycans or proteoglycans bound to A␤(1-28) affinity columns (29) or disassemble preformed A␤(1-40) fibrils (30). Thus, in addition to degrading the proteoglycan species that would otherwise be found in senile plaques, heparanases may be generating glycosaminoglycan species that act to prevent A␤ aggregation and deposition.…”

Section: Discussionmentioning

confidence: 99%

Aβ(1–40) Prevents Heparanase-catalyzed Degradation of Heparan Sulfate Glycosaminoglycans and Proteoglycans in Vitro

Bame

Danda

Hassall

et al. 1997

Journal of Biological Chemistry

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Alzheimer's disease is characterized by senile plaques composed of polymeric fibrils of beta amyloid (A␤), a 39 -42-amino acid peptide formed after proteolytic processing of the amyloid precursor protein (␤APP). Heparan sulfate proteoglycans have been shown to colocalize with A␤ in Alzheimer's disease brain, and experimental evidence indicates that the interactions between the proteoglycan and the peptide are important for the promotion, deposition, and/or persistence of the senile plaques. Studies in rat brain indicated that both the core protein and the heparan sulfate glycosaminoglycan chains are required for amyloid fiber formation and deposition in vivo (Snow, A. D., Sekiguchi, R., Nochlin, D., Fraser, P., Kimata, K., Mizutani, A., Arai, M., Schreier, W. A., and Morgan, D. G. (1994) Neuron 12, 219 -234), suggesting that one mechanism to prevent the formation of A␤-heparan sulfate proteoglycan complexes that lead to deposition of amyloid would be to degrade the proteoglycan. Normally, heparan sulfate proteoglycans are internalized and degraded to short glycosaminoglycans by intracellular heparanases. These reactions occur in the endosomal-lysosomal pathway, which is the same intracellular location where ␤APP is processed to A␤. Using partially purified heparanase activities from Chinese hamster ovary cells we examined whether A␤(1-40) affects the catabolism of Chinese hamster ovary heparan sulfate glycosaminoglycans and proteoglycans in vitro. A␤(1-40) binds to both the long heparan sulfate glycosaminoglycans attached to core proteins and the short, heparanase-derived chains in a concentration-dependent and pH-dependent manner. When A␤(1-40) is added to heparanase assays, it prevents the partially purified activities from releasing heparan sulfate chains from core proteins and degrading them to short glycosaminoglycans; however, a large molar excess of the peptide to heparan sulfate is required to see the effect. Our results suggest that normally the levels of A␤ in the endosomal pathway are not sufficient to interfere with heparanase activity in vivo. However, once the level of A␤-peptides are elevated, as they are in Alzheimer's disease, they could interact with heparan sulfate proteoglycans and prevent their catabolism. This could promote the formation and deposition of amyloid, since the binding of A␤ to the proteoglycan species will predominate.Histochemical and immunocytochemical studies have shown that heparan sulfate (HS) 1 proteoglycans (HSPGs) and glycosaminoglycans colocalize with ␤-amyloid protein (A␤) in the senile plaques characteristic of Alzheimer's disease (1). Although the precise role of the proteoglycans in the process of amyloidosis is not known, experimental evidence suggests that they may promote amyloid formation, deposition, and/or persistence (1) by binding to A␤ (2-5). HSPGs are anionic molecules consisting of one or more HS glycosaminoglycan chains covalently attached to a core protein (6). A␤ binds to HSPGs with high affinity, and interestingly, it interacts with both the core pr...

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“…Another set of GAG-based anti-amyloidogenic compounds has been designed according to their ionic properties. Kisilevsky et al [1995] reported that oral and ip administration of poly(vinylsufonate sodium salt), a small-molecule anionic sulfonate, inhibited splenic Ab deposition in a mouse model of inflammation-associated amyloid induction, under both acute and chronic conditions. A different GAG mimetic, 3-amino-1-propanesulfonic acid (Tramiprosate), binds soluble Ab 40 and Ab 42 peptides and maintains them in a random-coil conformation [Gervais et al, 2007].…”

Section: Glycosaminoglycan Mimeticsmentioning

confidence: 99%

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

Hawkes

McLaurin

2009

Drug Development Research

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Alzheimer disease (AD) is characterized pathologically by extracellular amyloid deposits composed of Ab peptide, neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau, and a deficit of cholinergic neurons in the basal forebrain. Presently, only symptomatic therapies are available for the treatment of AD and these therapies have a limited time frame of utility. Amyloid disorders represent the effects of chronic Ab production and are not a secondary pathological effect caused by a distant trigger; therefore targeting Ab is a viable pursuit. In this review, we will discuss the various small molecule antiaggregation inhibitors that have been reported in the literature, with emphasis on compounds that are presently being investigated in clinical trials. Drug Dev Res 70 : 111-124, 2009.

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Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease

Cited by 351 publications

References 26 publications

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

Aβ(1–40) Prevents Heparanase-catalyzed Degradation of Heparan Sulfate Glycosaminoglycans and Proteoglycans in Vitro

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

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