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The Journal of Neuroscience, February 2, 2005, 25(5):1219-1225; doi:10.1523/JNEUROSCI.4660-04.2005

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Neurobiology of Disease
Defective Neuromuscular Synapses in Mice Lacking Amyloid Precursor Protein (APP) and APP-Like Protein 2

Pei Wang,^1,2 * Guang Yang,^5 * Dennis R. Mosier,^3,6 Paul Chang,⁷ Tahire Zaidi,¹ Yan-Dao Gong,⁵ Nan-Ming Zhao,⁵ Bertha Dominguez,⁸ Kuo-Fen Lee,⁸ Wen-Biao Gan,⁷ and Hui Zheng^1,2,4

¹Huffington Center on Aging and Departments of ²Molecular and Cellular Biology, ³Neurology, and ⁴Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, ⁵Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China, ⁶Neurology and Medical Research Services, Veterans Administration Medical Center, Houston, Texas 77030, ⁷Molecular Neurobiology Program, Skirball Institute, New York University School of Medicine, New York, New York 10016, and ⁸The Salk Institute for Biological Studies, La Jolla, California 92037

Biochemical and genetic studies place the amyloid precursor protein (APP) at the center stage of Alzheimer's disease (AD) pathogenesis. Although mutations in the APP gene lead to dominant inheritance of familial AD, the normal function of APP remains elusive. Here, we report that the APP family of proteins plays an essential role in the development of neuromuscular synapses. Mice deficient in APP and its homolog APP-like protein 2 (APLP2) exhibit aberrant apposition of presynaptic marker proteins with postsynaptic acetylcholine receptors and excessive nerve terminal sprouting. The number of synaptic vesicles at presynaptic terminals is dramatically reduced. These structural abnormalities are accompanied by defective neurotransmitter release and a high incidence of synaptic failure. Our results identify APP/APLP2 as key regulators of structure and function of developing neuromuscular synapses.

Key words: Alzheimer's disease; amyloid precursor protein; neuromuscular junction; synaptic vesicles; synaptic transmission; knock-out mice

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Received Sep 14, 2004; revised December 21, 2004; accepted December 21, 2004.

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