Leandro H. Gallo, Nesar Akanda, Kaveena Autar, Aakash Patel, Ian Cox, Haley A. Powell, Marcella Grillo, Natali Barakat, Dave Morgan, Xiufang Guo, James J. Hickman
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引用次数: 0
Abstract
INTRODUCTION
The degeneration of cortical layers is associated with cognitive decline in Alzheimer's disease (AD). Current therapies for AD are not disease-modifying, and, despite substantial efforts, research and development for AD has faced formidable challenges. In addition, cellular senescence has emerged as a significant contributor to therapy resistance.
METHODS
Human iPSC-derived cortical neurons were cultured on microelectrode arrays to measure long-term potentiation (LTP) noninvasively. Neurons were treated with pathogenic amyloid-β (Aβ) to analyze senescence and response to therapeutic molecules.
RESULTS
Microphysiological recordings revealed Aβ dampened cortical LTP activity and accelerated neuronal senescence. Aging neurons secreted inflammatory factors previously detected in brain, plasma, and cerebral spinal fluid of AD patients, in which drugs modulated senescence-related factors.
DISCUSSION
This platform measures and records neuronal LTP activity in response to Aβ and therapeutic molecules in real-time. Efficacy data from similar platforms have been accepted by the FDA for neurodegenerative diseases, expediting regulatory submissions.
Highlights
This work developed a progerontic model of amyloid-β (Aβ)-driven cortical degeneration.
This work measured neuronal LTP and correlated function with aging biomarkers.
Aβ is a driver of neuronal senescence and cortical degeneration.
Molecules rescued neuronal function but did not halt Aβ-driven senescence.
Therapeutic molecules modulated secretion of inflammatory factors by aging neurons.
期刊介绍:
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.