TNFα-driven Aβ aggregation, synaptic dysfunction and hypermetabolism in human iPSC-derived cortical neurons

Abstract

Alzheimers disease (AD) patients exhibit an increased load of A{beta} aggregates in the brain parenchyma. The neurotoxic nature of these aggregates has been underscored by recent advances in therapies aimed at reducing their load. To make further progress towards the development of increasingly effective treatments, there is a still largely unmet need for reliable cell models that comprehensively recapitulate aggregate-driven AD pathology. Here, we report a robust and scalable pipeline for generating human iPSC-derived cortical neurons that display A{beta} aggregates in their axonal projections. This phenotype is caused by a repeated dosage of tumour necrosis factor-alpha (TNF) to simulate the chronic inflammatory environment characteristic of AD and enhanced in neurons carrying the Swedish mutation. In association with the increased A{beta} deposits in the cell bodies, this cell model exhibits other key hallmarks of AD, including structural alterations of synapses, electrophysiological asynchronous hyperactivity, and hypermetabolism. Overall, these results illustrate how repeated TNF treatment models central aspects of AD pathology, and provides a platform that could be used for facilitating the translation of potential drugs to clinical applications.