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Physiological Aβ Concentrations Produce a More Biomimetic Representation of the Alzheimer's Disease Phenotype in iPSC Derived Human Neurons. | LitMetric

AI Article Synopsis

  • - Alzheimer's disease (AD) leads to gradual nerve damage and serious cognitive decline, but research on effective treatments is hampered by inadequate disease models that accurately reflect human conditions.
  • - Current studies often use short exposure to high levels of amyloid-β (Aβ), which causes excessive neuron damage and doesn't accurately represent early AD stages.
  • - This research focuses on chronic exposure to lower Aβ concentrations, resulting in more accurate early-stage neuron dysfunction while avoiding severe cell death, which could enhance understanding of AD and aid in evaluating potential treatments.

Article Abstract

Alzheimer's disease (AD) is characterized by slow, progressive neurodegeneration leading to severe neurological impairment, but current drug development efforts are limited by the lack of robust, human-based disease models. Amyloid-β (Aβ) is known to play an integral role in AD progression as it has been shown to interfere with neurological function. However, studies into AD pathology commonly apply Aβ to neurons for short durations at nonphysiological concentrations to induce an exaggerated dysfunctional phenotype. Such methods are unlikely to elucidate early stage disease dysfunction, when treatment is still possible, since damage to neurons by these high concentrations is extensive. In this study, we investigated chronic, pathologically relevant Aβ oligomer concentrations to induce an electrophysiological phenotype that is more representative of early AD progression compared to an acute high-dose application in human cortical neurons. The high, acute oligomer dose resulted in severe neuronal toxicity as well as upregulation of tau and phosphorylated tau. Chronic, low-dose treatment produced significant functional impairment without increased cell death or accumulation of tau protein. This in vitro phenotype more closely mirrors the status of early stage neural decline in AD pathology and could provide a valuable tool to further understanding of early stage AD pathophysiology and for screening potential therapeutic compounds.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051921PMC
http://dx.doi.org/10.1021/acschemneuro.8b00067DOI Listing

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