{"id":575,"date":"2016-11-25T02:15:04","date_gmt":"2016-11-25T07:15:04","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=575"},"modified":"2016-11-25T02:15:35","modified_gmt":"2016-11-25T07:15:35","slug":"targeting-soluble-a-peptide-with-tramiprosate-for-the-treatment-of-brain-amyloidosis","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/targeting-soluble-a-peptide-with-tramiprosate-for-the-treatment-of-brain-amyloidosis\/","title":{"rendered":"Targeting soluble A\u03b2\u0002 peptide with Tramiprosate for the treatment of brain amyloidosis"},"content":{"rendered":"

The presence of amyloid deposits in the brain is one of the\u00a0major histopathological characteristics of Alzheimer\u2019s disease<\/a> (AD). The amyloid cascade hypothesis proposes\u00a0that the amyloid -peptide (A\u03b2)<\/a>, a major component of amyloid plaques, is causally related to AD neurodegeneration and\u00a0is a promising therapeutic target for disease-modifying treatment.<\/p>\n

The A\u03b2\u00a0peptide is produced from the sequential posttranslational processing of the amyloid precursor protein\u00a0(APP) by \u0002\u03b2-<\/a> and \u03b3-secretases<\/a>. Familial AD (FAD)\u00a0mutations within the human APP gene have been linked to\u00a0AD. These mutations appear to cause the disease by\u00a0increasing the processing of APP thereby augmenting the\u00a0total levels of A\u0002 or specifically favoring the production of\u00a0A\u03b242<\/sub>. The more hydrophobic A\u03b242 <\/sub>peptide has\u00a0been shown to be more fibrillogenic in vitro, to favor the\u00a0formation of assembly states thought to mediate neurotoxicity, and to facilitate the process of amyloid plaque deposition. Other FAD mutations have been linked to the\u00a0presenilin (PSEN) 1 and 2 genes and appear to favor the production of A\u03b242<\/sub>\u00a0peptides. Importantly, mice\u00a0harboring APP and\/or PSEN1\/PSEN2 with FAD mutation(s)\u00a0show a progressive increase in A\u03b2\u00a0levels and develop pathological\u00a0and behavioral changes reminiscent of those\u00a0observed in AD.<\/p>\n

Current anti-amyloid strategies are aimed at blocking the\u00a0processing of APP by targeting the \u03b2- and \u03b3-secretases\u00a0activities, the formation of amyloid fibrils, and amyloid-associated\u00a0neurotoxicity. Other recent approaches have attempted\u00a0to upregulate either the processing of APP by the \u03b3-secretase\u00a0(non-amyloidogenic pathway) or the clearance of the A\u03b2\u00a0peptides and associated amyloid deposits from the brain.\u00a0Anti-inflammatory agents with an effect on APP processing are also under investigation. Several other\u00a0approaches have been shown to reduce the amyloid load in\u00a0transgenic animal models\u00a0with a favorable effect on\u00a0cognitive function.<\/p>\n

Proteoglycans, a prominent constituent of amyloid\u00a0deposits, are implicated in amyloid fibril formation. The sulfated glycosaminoglycans (GAGs), a component of\u00a0the proteoglycans, contribute to fibrillogenesis by promoting the transition of A\u03b2\u0002from a random-coil to a \u03b2-sheet\u00a0rich conformation and protecting the fibrillar protein from\u00a0proteolysis. We have screened a series of\u00a0low-molecular weight (LMW) molecules that mimic the ionic\u00a0properties required for the binding of GAGs to A\u03b2. Our previous work revealed that such LMW molecules cross the\u00a0blood-brain barrier (BBB), are anti-fibrillogenic, and diminish A\u03b2-induced toxicity in SH-SY5Y neuronal cell cultures.<\/p>\n

Here we report that a specific ionic compound, Tramiprosate (3-amino-1-propanesulfonic acid; 3APS;\u00a0AlzhemedTM<\/sup>),\u00a0binds preferentially to soluble A\u03b2, maintains A\u03b2\u00a0in a randomcoil\/\u03b1-helical rich conformation, and reduces the amyloid\u00a0burden in TgCRND8 transgenic mice that develop earlyonset, aggressive brain amyloidosis. Targeting soluble\u00a0A\u0002 in vivo resulted in a dose-dependent reduction in both the\u00a0soluble and fibrillar amyloid burden in these mice. This new\u00a0class of drug represented by Tramiprosate holds promise for\u00a0the treatment of AD.<\/p>\n

 <\/p>\n

Reference:<\/h4>\n

Targeting soluble A\u03b2\u00a0peptide with Tramiprosate for the\u00a0treatment of brain amyloidosis.\u00a0Francine Gervais, Julie Paquette. Neurobiology of Aging 28 (2007) 537\u2013547<\/p>\n

 <\/p>\n

Related Products:<\/h4>\n
<\/div>
<\/th><\/th><\/th><\/th><\/th><\/tr><\/thead>
CAS Number <\/td>Product Name <\/td>Molecular Formula <\/td>Molecular Weight <\/td>Description <\/td><\/tr>
102212-26-0 <\/td>ARN2966<\/a><\/td>C12H12N2O <\/td>200.24 <\/td>ARN2966, also called 2-PMAP, as a Amyloid-\u03b2 inhibitor, is non toxic, orally absorbable, blood-brain-barrier penetrable, and effective in vitro and in vivo. <\/td><\/tr>
1193447-34-5 <\/td>CRANAD 2<\/a><\/td>C23H25BF2N2O2 <\/td>410.26 <\/td>CRANAD 2, a difluoroboron-derivatized curcumins, is a near-infrared (NIR) A\u03b2 plaque-specific fluorescent probe. It penetrates the blood-brain barrier and shows a high affinity for Abeta aggregates (K(d) = 38.0 nM). <\/td><\/tr>
35825-57-1 <\/td>Cryptotanshinone<\/a><\/td>C19H20O3 <\/td>296.36 <\/td>Cryptotanshinone, a natural cell-permeable diterpene quinone isolated from Salvia miltiorrhiza, it inhibits acetylcholinesterase (IC50 = 4.09 \u03bcM) and reduces A\u03b2 peptide generation so that can treat Alzheimer's disease. It also inhibits STAT3 activity (IC50 = 4.6 \u03bcM). <\/td><\/tr>
317366-82-8 <\/td>Amyloid \u03b2-peptide (42-1) (human)<\/a><\/td>C203H311N55O60S <\/td>4514.08 <\/td>Amyloid \u03b2-peptide (42-1) (human), is the predominant form of amyloid \u03b2-peptide found in the brains of patients with Alzheimer's disease. <\/td><\/tr>
145915-58-8 <\/td>CGP 52411<\/a><\/td>C20H15N3O2 <\/td>329.35 <\/td>CGP 52411, also called DAPH, inhibits and reverses the formation of A\u03b242 fibers (\u03b2-sheet content of aggregated \u03b2-amyloid (1-42): IC50 = 4.5 \u00b5M) in neurons associated with Alzheimer's disease. And it is also a selective inhibitor of the epidermal growth factor receptor (EGFR) (IC50 = 0.3 \u03bcM in vitro). <\/td><\/tr><\/tbody><\/table><\/div>\n","protected":false},"excerpt":{"rendered":"

The presence of amyloid deposits in the brain is one of the\u00a0major histopathological characteristics of Alzheimer\u2019s disease (AD). The amyloid cascade hypothesis proposes\u00a0that the amyloid -peptide (A\u03b2), a major component […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[225],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/575"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=575"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/575\/revisions"}],"predecessor-version":[{"id":576,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/575\/revisions\/576"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=575"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=575"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=575"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}