Physiological Aβ Concentrations Produce A More Biomimetic Representation Of The Alzheimer'S Disease Phenotype In Ipsc Derived Human Neurons

Keywords

Alzheimer's disease; Aβ oligomers; chronic; electrophysiology; human

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.

Publication Date

7-18-2018

Publication Title

ACS Chemical Neuroscience

Volume

9

Issue

7

Number of Pages

1693-1701

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/acschemneuro.8b00067

Socpus ID

85046960589 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85046960589

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