Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2.
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.
Wang
Pei
P
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.
Yang
Guang
G
Mosier
Dennis R
DR
Chang
Paul
P
Zaidi
Tahire
T
Gong
Yan-Dao
YD
Zhao
Nan-Ming
NM
Dominguez
Bertha
B
Lee
Kuo-Fen
KF
Gan
Wen-Biao
WB
Zheng
Hui
H
D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers; D003964:Diaphragm / Q000737:chemistry / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009045:Motor Endplate / Q000737:chemistry / Q000648:ultrastructure; D009124:Muscle Proteins / Q000737:chemistry; D009334:Neck Muscles / Q000737:chemistry / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000196:embryology / Q000378:metabolism*; D010641:Phenotype; D011950:Receptors, Cholinergic / Q000737:chemistry; D017661:Receptors, Presynaptic / Q000737:chemistry; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000737:chemistry
D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D015415:Biomarkers; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D017661:Receptors, Presynaptic