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The Journal of Neuroscience, July 30, 2003, 23(17):6788-6792

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BRIEF COMMUNICATION
App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome

Anne M. Cataldo,^1,2,3 Suzana Petanceska,³ Corrinne M. Peterhoff,³ Nicole B. Terio,³ Charles J. Epstein,⁴ Angela Villar,⁴ Elaine J. Carlson,⁵ Matthias Staufenbiel,⁶ and Ralph A. Nixon^3,7

¹Mailman Research Center, McLean Hospital, Belmont, Massachusetts 02478, ²Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, ³Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962, ⁴Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, ⁵Genomics Core Facility, University of California, San Francisco, San Francisco, California 94143, ⁶Novartis Institute of Biomedical Research, Nervous System, CH-4002 Basel, Switzerland, and ⁷Departments of Psychiatry and Cell Biology, New York University School of Medicine, New York, New York 10016

Altered neuronal endocytosis is the earliest known pathology in sporadic Alzheimer's disease (AD) and Down syndrome (DS) brain and has been linked to increased A production. Here, we show that a genetic model of DS (trisomy 21), the segmental trisomy 16 mouse Ts65Dn, develops enlarged neuronal early endosomes, increased immunoreactivity for markers of endosome fusion (rab5, early endosomal antigen 1, and rabaptin5), and endosome recycling (rab4) similar to those in AD and DS individuals. These abnormalities are most prominent in neurons of the basal forebrain, which later develop aging-related atrophy and degenerative changes, as in AD and DS. We also show that App, one of the triplicated genes in Ts65Dn mice and human DS, is critical to the development of these endocytic abnormalities. Selectively deleting one copy of App or a small portion of the chromosome 16 segment containing App from Ts65Dn mice eliminated the endosomal phenotype. Overexpressing App at high levels in mice did not alter early endosomes, implying that one or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype. These results identify an essential role for App gene triplication in causing AD-related endosomal abnormalities and further establish the pathogenic significance of endosomal dysfunction in AD.

Key words: endosomes; endocytic pathway; Ts65Dn; Ts1Cje; Down syndrome; Alzheimer's disease; amyloid precursor protein; basal forebrain neurons

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Received Apr. 7, 2003; revised Apr. 7, 2003; accepted May. 14, 2003.

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