title: Beta-amyloid oligomers induce early loss of presynaptic proteins in primary neurons by caspase-dependent and proteasome-dependent mechanisms.
abstract: Beta-amyloid is a major pathogenic molecule for Alzheimer's disease (AD) and can be aggregated into a soluble oligomer, which is a toxic intermediate, before amyloid fibril formation. Beta-amyloid oligomers are associated closely with early synaptic loss in AD. However, it is still unknown which synaptic proteins are involved in the synaptotoxicity, and a direct comparison among the synaptic proteins should also be addressed. Here, we investigated changes in the expression of several presynaptic and postsynaptic proteins in primary neurons after treatment with a low-molecular weight and a high-molecular weight beta-amyloid oligomer. Both oligomers induced early neuronal dysfunction after 4 h and significantly reduced presynaptic protein (synaptophysin, syntaxin, synapsin, and synaptotagmin) expression. However, the expression of postsynaptic proteins (PSD95, NMDAR2A/B, and GluR2/3), except NMDAR1 was not reduced, and some protein expression levels were increased. Glutamate treatment, which is correlated with postsynaptic activation, showed more postsynaptic-specific protein loss compared with beta-amyloid oligomer treatment. Finally, the caspase inhibitor zVAD and the proteasomal inhibitor MG132 attenuated presynaptic protein loss. Thus, our data showed changes in synaptic proteins by beta-amyloid oligomers, which provides an understanding of early synaptotoxicity and suggests new approaches for AD treatment.
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Gangwon-Do, Korea.
authors.forename: Bong Geum
authors.initials: BG
authors.lastname: Jang
authors.forename: Sua
authors.initials: S
authors.lastname: In
authors.forename: Boyoung
authors.initials: B
authors.lastname: Choi
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Kim
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005971:Glutamates / Q000494:pharmacology; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D005971:Glutamates; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D061988:Proteasome Inhibitors; D033921:Vesicular Transport Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D020169:Caspases; D046988:Proteasome Endopeptidase Complex