ArticlePloS one2010
HH domain of Alzheimer's disease Abeta provides structural basis for neuronal binding in PC12 and mouse cortical/hippocampal neurons.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 22 citations in OpenAlex.
- An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2012Trial
- Key Residue for Aggregation of Amyloid-β Peptides.ACS chemical neuroscience · 2022Article
- Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.Neurobiology of disease · 2018Article
- Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function.Neurobiology of aging · 2014Article
- Modulation of amyloid-β aggregation by histidine-coordinating Cobalt(III) Schiff base complexes.Chembiochem : a European journal of chemical biology · 2014Article
- Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease.Neurobiology of aging · 2013Article
- Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?Immunity & ageing : I & A · 2013Article
- Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation.The Journal of biological chemistry · 2012Article
- Differences in the cellular uptake and intracellular itineraries of amyloid beta proteins 40 and 42: ramifications for the Alzheimer's drug discovery.Molecular pharmaceutics · 2012Article
- Article
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Authors and funding
7 authors at 2 institutions in 1 country.
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Abstract
A key question in understanding AD is whether extracellular Abeta deposition of parenchymal amyloid plaques or intraneuronal Abeta accumulation initiates the AD process. Amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce soluble Abeta which is then released into the brain interstitial fluid. Intraneuronal Abeta accumulation is hypothesized to predominate from the neuronal uptake of this soluble extracellular Abeta rather than from ER/Golgi processing of APP. We demonstrate that substitution of the two adjacent histidine residues of Abeta40 results in a significant decrease in its binding with PC12 cells and mouse cortical/hippocampal neurons. These substitutions also result in a dramatic enhancement of both thioflavin-T positive fibril formation and binding to preformed Abeta fibrils while maintaining its plaque-binding ability in AD transgenic mice. Hence, alteration of the histidine domain of Abeta prevented neuronal binding and drove Abeta to enhanced fibril formation and subsequent amyloid plaque deposition--a potential mechanism for removing toxic species of Abeta. Substitution or even masking of these Abeta histidine residues might provide a new therapeutic direction for minimizing neuronal uptake and subsequent neuronal degeneration and maximizing targeting to amyloid plaques.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.