Neuritic Deposits of Amyloid-β Peptide in a Subpopulation of Central Nervous System-Derived Neuronal Cells

Abstract

Our goal is to understand the pathogenesis of amyloid-β (Aβ) deposition in the Alzheimer's disease (AD) brain. We established a cell culture system where central nervous system-derived neuronal cells (CAD cells) produce and accumulate within their processes large amounts of Aβ peptide, similar to what is believed to occur in brain neurons, in the initial phases of AD. Using this system, we show that accumulation of Aβ begins within neurites, prior to any detectable signs of neurodegeneration or abnormal vesicular transport. Neuritic accumulation of Aβ is restricted to a small population of neighboring cells that express normal levels of amyloid-β precursor protein (APP) but show redistribution of BACE1 to the processes, where it colocalizes with Aβ and markers of late endosomes. Consistently, cells that accumulate Aβ appear in isolated islets, suggesting their clonal origin from a few cells that show a propensity to accumulate Aβ. These results suggest that Aβ accumulation is initiated in a small number of neurons by intracellular determinants that alter APP metabolism and lead to Aβ deposition and neurodegeneration. CAD cells appear to recapitulate the biochemical processes leading to Aβ deposition, thus providing an experimental in vitro system for studying the molecular pathobiology of AD.

This work was supported by National Institutes of Health grant 5RO1GM068596-02 and a Mt. Sinai Health Care Foundation scholarship (V.M.).

We thank Dona Chikaraishi and James Wang for kindly providing the CAD cell line; Samantha Cicero and Karl Herrup for kindly providing the cortical neuron cultures; and Li-Huei Tsai, Ming-Sum Lee, Bruce Lamb, and Riqiang Yan for kindly providing cDNA constructs and antibodies. We also thank Karl Herrup and Bruce Lamb for many fruitful discussions on topics covered in this paper.