Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Aβ(25–35)-induced abnormal tau protein immunoreactivity in rat brain

Dudás, Bertalan; Cornelli, Umberto; Lee, J.M; Hejna, Matthew J.; Walzer, Mark; Lorens, Stanley A.; Mervis, Ronald F.; Fareed, Jawed; Hanin, Israel

doi:10.1016/s0197-4580(01)00255-x

Cited by 41 publications

(17 citation statements)

References 54 publications

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“…Interestingly, treatment of rats with certoparin or its derivative C6, either before or after intra-amygdaloid infusion of Ab, blocked Ab-associated changes to intracellular tau and reduced astrogliosis, without altering Ab aggregation . Similar findings were also reported by Dudas et al [2002] using the C3 derivative, which protects against Ab-induced increases in tau-2-immunoreactivity in hippocampal neurons. Another set of GAG-based anti-amyloidogenic compounds has been designed according to their ionic properties.…”

Section: Glycosaminoglycan Mimeticssupporting

confidence: 89%

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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Section: Glycosaminoglycan Mimeticssupporting

confidence: 89%

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

Hawkes

McLaurin

2009

Drug Development Research

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“…It is hypothesized that these agents may exert their therapeutic effects by interfering with the proteoglycan-induced amyloid and tau abnormality in AD. Recent studies have supported this hypothesis showing that low molecular weight heparins and related oligosaccharides are capable of attenuating proteoglycan-associated tau toxicity in rat brain [83][84].…”

Section: Resultsmentioning

confidence: 84%

“…A significant decrease of tau toxicity by certoparin was observed among treated animals [83]. Using the same animal model, Dudas et al demonstrated the protective effects of a heparin oligosaccharide mixture on the brain after the injection of amyloid peptide into the amygdale [84].…”

Section: Heparin Oligosaccharides and Alzheimer's Diseasementioning

confidence: 94%

Heparin Oligosaccharides as Potential Therapeutic Agents in Senile Dementia

Ma¹,

Cornelli²,

Hanin³

et al. 2007

CPD

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Heparin is a glycosaminoglycan mixture currently used in prophylaxis and treatment of thrombosis. Heparin possesses non-anticoagulant properties, including modulation of various proteases, interactions with fibroblast growth factors, and anti-inflammatory actions. Senile dementia of Alzheimer's type is accompanied by inflammatory responses contributing to irreversible changes in neuronal viability and brain function. Vascular factors are also involved in the pathogenesis of senile dementia. Inflammation, endogenous proteoglycans, and assembly of senile plagues and neurofibrillary tangles contribute directly and indirectly to further neuronal damage. Neuron salvage can be achieved by anti-inflammation and the competitive inhibition of proteoglycans accumulation. The complexity of the pathology of senile dementia provides numerous potential targets for therapeutic interventions designed to modulate inflammation and proteoglycan assembly. Heparin and related oligosaccharides are known to exhibit antiinflammatory effects as well as inhibitory effects on proteoglycan assembly and may prove useful as neuroprotective agents.

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“…One week after Ab [25][26][27][28][29][30][31][32][33][34][35] injection, APP and Ab 1-42 levels were increased in the hippocampus and cortex, Ab-expressing cells could be visualized using immunohistochemistry and b-secretase cleavage products, such as the C-terminal fragment C99, could be detected (Klementiev et al, 2007;Chavant et al, 2010;Zussy et al, 2011). Moreover, an increase in Tau phosphorylation on physiological or AD-related pathological epitopes induced by Ab 25-35 injection in mice was reported in several studies (Dudas et al, 2002;Klementiev et al, 2007;Deng et al, 2010). The model indeed appeared highly suitable to analyze the time course of kinase activations (Akt and GSK-3b) within days after Ab injection and the resulting induction of Tau hyper-and abnormal phosphorylation.…”

Section: Introductionmentioning

confidence: 77%

Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease

Lahmy

Meunier²,

Malmström³

et al. 2013

Neuropsychopharmacol

138

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The main objective of the present study was to establish whether the mixed s 1 /muscarinic ligand ANAVEX2-73, shown to be neuroprotective in Alzheimer's disease (AD) models in vivo and currently in clinical phase I/IIa, could have the ability to reduce the appearance of hyperphosphorylated Tau and amyloid-b 1-42 (Ab 1-42 ) in the Ab 25-35 mouse model of AD. We therefore first confirmed that Ab 25-35 injection induced hyperphosphorylation of Tau protein, by showing that it rapidly decreased Akt activity and activated glycogen synthase kinase-3b (GSK-3b) in the mouse hippocampus. Second, we showed that the kinase activation, and resulting Tau alteration, directly contributed to the amyloid toxicity, as co-administration of the selective GSK-3b inhibitor 2-thio(3-iodobenzyl)-5-(1-pyridyl)-[1,3,4]-oxidiazole blocked both Tau phosphorylation and Ab 25-35 -induced memory impairments. Third, we analyzed the ANAVEX2-73 effect on Tau phosphorylation and activation of the related kinase pathways (Akt and GSK-3b). And fourth, we also addressed the impact of the drug on Ab 25-35 -induced Ab 1-42 seeding and observed that the compound significantly blocked the increase in Ab 1-42 and C99 levels in the hippocampus, suggesting that it may alleviate amyloid load in AD models. The comparison with PRE-084, a selective and reference s 1 receptor agonist, and xanomeline, a muscarinic ligand presenting similar profile as ANAVEX2-73 on M1 and M2 subtypes, confirmed that both muscarinic and s 1 targets are involved in the ANAVEX2-73 effects. The drug, acting synergistically on both targets, but with moderate affinity, presents a promising pharmacological profile.

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Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Aβ(25–35)-induced abnormal tau protein immunoreactivity in rat brain

Cited by 41 publications

References 54 publications

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

Heparin Oligosaccharides as Potential Therapeutic Agents in Senile Dementia

Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease

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