Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 26, Issue 13, Pages 4982-4997Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00371-06
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Funding
- NIGMS NIH HHS [R01 GM068596, 5R01GM068596-02] Funding Source: Medline
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Our goal is to understand the pathogenesis of amyloid-beta (A beta) 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 A beta 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 A beta begins within neurites, prior to any detectable signs of neurodegeneration or abnormal vesicular transport. Neuritic accumulation of A beta is restricted to a small population of neighboring cells that express normal levels of amyloid-beta precursor protein (APP) but show redistribution of BACE1 to the processes, where it colocalizes with A beta and markers of late endosomes. Consistently, cells that accumulate A beta appear in isolated islets, suggesting their clonal origin from a few cells that show a propensity to accumulate A beta. These results suggest that A beta accumulation is initiated in a small number of neurons by intracellular determinants that alter APP metabolism and lead to A beta deposition and neurodegeneration. CAD cells appear to recapitulate the biochemical processes leading to A beta deposition, thus providing an experimental in vitro system for studying the molecular pathobiology of A beta.
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