Regulation of Aβ40 and Aβ42 by formaldehyde exposure in a three‐dimensional (3D) human neural cell culture model for Alzheimer's Disease

Abstract

Alzheimer's disease (AD), a chronic neurodegenerative disorder characterized by rapidly progressive cognitive dysfunction and behavior impairment, is the most common form of dementia which accounts for 60 to 70 percent of cases. Pathologically, AD is characterized by severe atrophy and neuronal loss, extracellular neuritic plaques composed mainly of aggregated amyloid-b (Ab), and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. Multilevel complex interactions between genetic, epigenetic, and environmental factors contribute to the occurrence and progression of AD. Formaldehyde (FA) is the simplest saturated aldehyde which is one of the most typical environmental and occupational aldehyde pollutants. Recent studies suggested that elevation of FA in the brain, blood or urine by endogenous and/or exogenous exposure may play important roles in AD development. A three-dimensional (3D) human neural cell culture model for AD which can recapitulate key events of AD pathology including β-amyloid plaques and neurofibrillary tangles was used to investigate the effect of FA exposure in AD development and progression in human cells. Immortalized human neural progenitor cells (ReNcell VM (ReN)) were virally transfected with AD-related mutant genes including mutant APP and/or PSEN1 and enriched based on GFP and/or mCherry signals by Fluorescence-activated cell sorting (FACS). In order to mimic the restrictive environment of human brain and allow Aβ deposition and aggregation, the FACS-sorted ReN cells were differentiated into neurons and maintained in a 3D Matrigel culture system. The AD Model and primary ReN cells were treated with different concentrations of FA as well as vehicle controls for 16 weeks. Expression of Aβ40 and Aβ42 were measured in 4, 6, 12 16 weeks by ELISA and cytotoxicity was evaluated by LDH activity assay. The results revealed that FA significantly elevates expression of Aβ40 and Aβ42 in a concentration-dependent manner both in AD model and ReN cells. It indicated that FA exposure may play a critical role in AD development and progression.