Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyloid beta-Protein Precursor / deficiency
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / physiology*
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Animals
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Animals, Newborn
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Biomarkers
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Diaphragm / chemistry
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Diaphragm / ultrastructure
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Mice
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Mice, Knockout
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Mice, Neurologic Mutants
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Motor Endplate / chemistry
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Motor Endplate / ultrastructure
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Muscle Proteins / chemistry
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Neck Muscles / chemistry
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Neck Muscles / ultrastructure
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Neuromuscular Junction / embryology
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Neuromuscular Junction / metabolism*
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Phenotype
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Receptors, Cholinergic / chemistry
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Receptors, Presynaptic / chemistry
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Synaptic Transmission
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Synaptic Vesicles / chemistry
Substances
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Amyloid beta-Protein Precursor
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Aplp2 protein, mouse
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Biomarkers
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Muscle Proteins
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Receptors, Cholinergic
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Receptors, Presynaptic