Laminin affects polymerization, depolymerization and neurotoxicity of Aβ peptide

Morgan, Carlos; Bugueño, Manuel P.; Garrido, Jorge; Inestrosa, Nibaldo C.

doi:10.1016/s0196-9781(02)00058-x

Cited by 38 publications

(37 citation statements)

References 82 publications

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“…Observations were carried out using Philips Tecnai 12 electron microscope, as described previously. 6 The quantification of amyloid aggregates and fibrils was made using Sigma Scan Pro software. 16 …”

Section: Electron Microscopymentioning

confidence: 99%

“…[2][3][4] It has been proposed that Ab aggregation would require inherent depolymerization mechanisms in order to explain the morphology and the stable size of the senile plaques observed in AD, 5 which indicates that amyloidogenesis is a continuous process of polymerization and depolymerization. 6 As Ab is toxic to neurons, 7 the main targets for therapeutic intervention of the Ab cascade include the inhibition of Ab production, the inhibition of Ab aggregation and fibril formation, in addition to the inhibition of the consequent inflammatory responses caused by the Ab deposition. In this context, several substances are known to inhibit Ab fibrillogenesis in vitro, including laminin, 6,8 melatonin, 9 nordihydroguaiaretic acid, 10 polyphenols, 11 site-directed monoclonal antibodies, 12 a1-antichymotrypsin, 13 Ginkgo biloba extract, 14 type IV collagen 15 and b-sheet breaker peptides.…”

Section: Introductionmentioning

confidence: 99%

“…6 As Ab is toxic to neurons, 7 the main targets for therapeutic intervention of the Ab cascade include the inhibition of Ab production, the inhibition of Ab aggregation and fibril formation, in addition to the inhibition of the consequent inflammatory responses caused by the Ab deposition. In this context, several substances are known to inhibit Ab fibrillogenesis in vitro, including laminin, 6,8 melatonin, 9 nordihydroguaiaretic acid, 10 polyphenols, 11 site-directed monoclonal antibodies, 12 a1-antichymotrypsin, 13 Ginkgo biloba extract, 14 type IV collagen 15 and b-sheet breaker peptides. 16 Nevertheless, an effective therapeutic approach that interferes directly with the neurodegenerative process in AD is eagerly awaited.…”

Section: Introductionmentioning

confidence: 99%

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Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Dinamarca¹,

Cerpa²,

Garrido

et al. 2006

Mol Psychiatry

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The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid b-peptide (Ab). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Ab-induced spatial memory impairments and on Ab neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Ab-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Ab oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Ab aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.

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Section: Electron Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Dinamarca¹,

Cerpa²,

Garrido

et al. 2006

Mol Psychiatry

View full text Add to dashboard Cite

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“…15,[20][21][22] Morgan et al have shown that laminin-1 can cause complete disassembly of fibrils into protofilaments and amorphous aggregates. 23 Fibril disaggregation induced by laminin-1 also contributed to the prevention of amyloid toxicity on hippocampal neuronal cells. Khlistunova et al 15 observed that expression of the repeat domain of tau in N2a cell lines led to robust aggregation of tau and formation of Alzheimer-like paired helical filaments with high cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

In Silicoandin VitroStudy of Binding Affinity of Tripeptides to Amyloid β Fibrils: Implications for Alzheimer’s Disease

et al. 2015

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Self-assembly of Aβ peptides into amyloid aggregates has been suggested as the major cause of Alzheimer's disease (AD). Nowadays, there is no medication for AD, but experimental data indicate that reversion of the process of amyloid aggregation reduces the symptoms of disease. In this paper, all 8000 tripeptides were studied for their ability to destroy Aβ fibrils. The docking method and the more sophisticated MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method were employed to calculate the binding affinity and mode of tripeptides to Aβ fibrils. The ability of these peptides to depolymerize Aβ fibrils was also investigated experimentally using atomic force microscopy and fluorescence spectroscopy (Thioflavin T assay). It was shown that tripeptides prefer to bind to hydrophobic regions of 6Aβ9-40 fibrils. Tripeptides WWW, WWP, WPW and PWW were found to be the most potent binders. In vitro experiments showed that tight-binding tripeptides have significant depolymerizing activities and their DC50 values determined from dose-response curves were in micromolar range. The ability of nonbinding (GAM, AAM) and weak-binding (IVL and VLA) tripeptides to destroy Aβ fibrils was negligible. In vitro data of tripeptide depolymerizing activities support the predictions obtained by molecular docking and all-atom simulation methods. Our results suggest that presence of multiple complexes of heterocycles forming by tryptophan and proline residues in tripeptides is crucial for their tight binding to Aβ fibrils as well as for extensive fibril depolymerization. We recommend PWW for further studies as it has the lowest experimental binding constant.

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“…[4][5][6][7][8] However, the clinic study was halted because the human vaccination induced a severe brain inflammatory response, 9,10 which can be related to cerebral hemorrhages observed after passive anti-Ab immunotherapy in APP23 transgenic mice. 11 In addition, several molecules have been used either to inhibit polymerization of Ab peptides or to disaggregate Ab fibrils, including laminin 12,13 melatonin, 14 nordihydroguaiaretic acid, 15 polyphenols, 16 site-directed monoclonal antibodies, 17 a 1 -antichymotrypsin, 18 fullerene, 19 Ginkgo biloba extract, 20 type IV collagen, 21 short Ab congeners 22 and b-sheet breaker peptides. [23][24][25] b-sheet breaker peptides have both a similar sequence to the middle region of Ab peptide and degree of hydrophobicity, but have a very low propensity to adopt a b-sheet conformation, which is responsible for the aggregation properties and the consequent neurotoxicity.…”

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confidence: 99%

β-sheet breaker peptide prevents Aβ-induced spatial memory impairments with partial reduction of amyloid deposits

et al. 2004

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Current evidence supports the notion that b-amyloid deposits or Ab intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid b-sheet breaker peptide (iAb5p) on the rat behavioral deficit induced by the intrahippocampal Ab-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAb5p treatment, hippocampaldependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Ab deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with b-sheet breaker peptides may be used as a potential therapy for AD patients. Molecular Psychiatry (2004) 9, 953-961.

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Laminin affects polymerization, depolymerization and neurotoxicity of Aβ peptide

Cited by 38 publications

References 82 publications

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

In Silicoandin VitroStudy of Binding Affinity of Tripeptides to Amyloid β Fibrils: Implications for Alzheimer’s Disease

β-sheet breaker peptide prevents Aβ-induced spatial memory impairments with partial reduction of amyloid deposits

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