Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines.
Synapse loss induced by amyloid beta (Abeta) is thought to be a primary contributor to cognitive decline in Alzheimer's disease. Abeta is generated by proteolysis of amyloid precursor protein (APP), a synaptic receptor whose physiological function remains unclear. In the present study, we investigated the role of APP in dendritic spine formation, which is known to be important for learning and memory. We found that overexpression of APP increased spine number, whereas knockdown of APP reduced spine density in cultured hippocampal neurons. This spine-promoting effect of APP required both the extracellular and intracellular domains of APP, and was accompanied by specific upregulation of the GluR2, but not the GluR1, subunit of AMPA receptors. In an in vivo experiment, we found that cortical layers II/III and hippocampal CA1 pyramidal neurons in 1 year-old APP-deficient mice had fewer and shorter dendritic spines than wild-type littermates. In contrast, transgenic mice overexpressing mutant APP exhibited increased spine density compared to control animals, though only at a young age prior to overaccumulation of soluble amyloid. Additionally, increased glutamate synthesis was observed in young APP transgenic brains, whereas glutamate levels were decreased and GABA levels were increased in APP-deficient mice. These results demonstrate that APP is important for promoting spine formation and is required for proper spine development.
Lee
K J
KJ
Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057-1464, USA.
Moussa
C E H
CE
Lee
Y
Y
Sung
Y
Y
Howell
B W
BW
Turner
R S
RS
Pak
D T S
DT
Hoe
H S
HS
D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001923:Brain Chemistry; D019556:COS Cells; D002478:Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000096:biosynthesis; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D017966:Pyramidal Cells / Q000187:drug effects / Q000648:ultrastructure; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D016564:Amyloid beta-Protein Precursor; D018698:Glutamic Acid; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D005680:gamma-Aminobutyric Acid; C104722:glutamate receptor ionotropic, AMPA 2
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