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

• DOI: 10.1523/jneurosci.4660-04.2005
• Publication Date: 2005-02-02T20:40:28Z
• Authors: Pei Wang; Guang Yang; Dennis R. Mosier; Paul Chang; Tahire Zaidi; Yan-Dao Gong; Nan-Ming Zhao; Bertha Dominguez; Kuo-Fen Lee; Wen-Biao Gan; Hui Zheng
• Keywords: Mice, Knockout; 0301 basic medicine; Diaphragm; Neuromuscular Junction; Muscle Proteins; Receptors, Presynaptic; Motor Endplate; Synaptic Transmission; 3. Good health; Amyloid beta-Protein Precursor; Mice; Mice, Neurologic Mutants; 03 medical and health sciences; Phenotype; Animals, Newborn; Neck Muscles; Animals; Receptors, Cholinergic; Synaptic Vesicles; Biomarkers

Biochemical and genetic studies place the amyloid precursor protein (APP) at the center stage of Alzheimer's disease (AD) pathogenesis. Although mutations in theAPPgene 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 inAPPand 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.