Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations.
A central question in Alzheimer's disease research is what role synaptic activity plays in the disease process. Synaptic activity has been shown to induce beta-amyloid peptide release into the extracellular space, and extracellular beta-amyloid has been shown to be toxic to synapses. We now provide evidence that the well established synaptotoxicity of extracellular beta-amyloid requires gamma-secretase processing of amyloid precursor protein. Recent evidence supports an important role for intraneuronal beta-amyloid in the pathogenesis of Alzheimer's disease. We show that synaptic activity reduces intraneuronal beta-amyloid and protects against beta-amyloid-related synaptic alterations. We demonstrate that synaptic activity promotes the transport of the amyloid precursor protein to synapses using live cell imaging, and that the protease neprilysin is involved in reduction of intraneuronal beta-amyloid with synaptic activity.
Tampellini
Davide
D
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065, USA.
Rahman
Nawreen
N
Gallo
Eduardo F
EF
Huang
Zhenyong
Z
Dumont
Magali
M
Capetillo-Zarate
Estibaliz
E
Ma
Tao
T
Zheng
Rong
R
Lu
Bao
B
Nanus
David M
DM
Lin
Michael T
MT
Gouras
Gunnar K
GK
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D005110:Extracellular Space / Q000378:metabolism; D051528:Guanylate Kinases; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C075222:amyloid beta-protein (1-42); D051528:Guanylate Kinases; D053829:Amyloid Precursor Protein Secretases; D015260:Neprilysin