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Article type: Research Article
Authors: Liu, Jinpinga | Chang, Lironga | Roselli, Francescob; c | Almeida, Osborne F.X.b | Gao, Xiulaia | Wang, Xiaomind | Yew, David T.e | Wu, Yana; b; *
Affiliations: [a] Department of Anatomy, Capital Medical University, Beijing, China | [b] Max Planck Institute of Psychiatry, Munich, Germany | [c] Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy | [d] Department of Physiology, Capital Medical University, Beijing, China | [e] Chinese University of Hong Kong, Shatin, N.T., Hong Kong
Correspondence: [*] Correspondence to: Yan Wu, Department of Anatomy, Capital Medical University, Beijing 100069, China. Tel.: +86 10 83911446 804; Fax: +86 10 83911443; E-mail: [email protected].
Note: [] Handling Associate Editor: Xiaochun Chen
Abstract: Soluble oligomeric amyloid-β (Aβ) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Aβ downregulates the levels of two synaptic proteins, PSD-95 and synaptophysin, and that this effect can be blocked by MK-801 (NMDAR antagonist) and ifenprodil (NR2B antagonist). Low (1 μM) and high (10 μM) doses of NMDA, respectively, prevented and potentiated the actions of Aβ. Blockade of NR2A or synaptic NMDAR eliminated the protective effect of 1 μM NMDA, while the effects of 10 μM NMDA were only abolished by ifenprodil. Caspase-8, acting upstream of caspase-3, was found to mediate the synaptotoxic actions of Aβ in an ifenprodil-reversible fashion. Thus, Aβ leads to a loss of synaptic proteins by suppression of NR2A function and activation of NR2B function and subsequent induction of caspase-8 and caspase-3 activities. The identified novel mechanism through which Aβ initiates synaptic dysfunction suggests that selective enhancement of NR2A activity and/or reduction of NR2B activity can halt the manifestation of a key early-stage event in AD.
Keywords: Alzheimer's disease, amyloid-β peptide, caspase, hippocampus, NMDA receptor
DOI: 10.3233/JAD-2010-100948
Journal: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 541-556, 2010
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