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Molecular and Cellular Biology, July 2006, p. 4982-4997, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.00371-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Zoia Muresan and Virgil Muresan*

Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970

Received 1 March 2006/ Returned for modification 4 April 2006/ Accepted 18 April 2006

Our goal is to understand the pathogenesis of amyloid-ß (Aß) 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 Aß 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 Aß begins within neurites, prior to any detectable signs of neurodegeneration or abnormal vesicular transport. Neuritic accumulation of Aß is restricted to a small population of neighboring cells that express normal levels of amyloid-ß precursor protein (APP) but show redistribution of BACE1 to the processes, where it colocalizes with Aß and markers of late endosomes. Consistently, cells that accumulate Aß appear in isolated islets, suggesting their clonal origin from a few cells that show a propensity to accumulate Aß. These results suggest that Aß accumulation is initiated in a small number of neurons by intracellular determinants that alter APP metabolism and lead to Aß deposition and neurodegeneration. CAD cells appear to recapitulate the biochemical processes leading to Aß deposition, thus providing an experimental in vitro system for studying the molecular pathobiology of AD.

* Corresponding author. Mailing address: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4970. Phone: (216) 368-4766. Fax: (216) 368-3952. E-mail: virgil.muresan{at}case.edu.

Molecular and Cellular Biology, July 2006, p. 4982-4997, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.00371-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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