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P4‐265: Changes of synaptic ultrastructure, synaptophysin and choline acetyltransferase in hippocampus of age‐increasing rats
Author(s) -
Wang Rong,
Li Lin,
Tang Yu,
Zhang Lan
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.2334
Subject(s) - synaptophysin , morris water navigation task , hippocampus , hippocampal formation , water maze , choline acetyltransferase , neuroscience , synaptic vesicle , endocrinology , medicine , chemistry , biology , psychology , immunohistochemistry , cholinergic , vesicle , biochemistry , membrane
amyloid plaques, pre-fibrillar small oligomeric amyloid intermediates may be the most neurotoxic species. Notably oligomers from diverse diseaserelated amyloids share a remarkably similar quaternary structure and are equally cytotoxic, suggesting common mechanisms of action. With this in mind, we investigated the role of calcineurin (CaN), a protein phosphatase abundant in neurons and involved in synaptic plasticity and neuronal death, in mediating the cytotoxic and cognitive effects of various amyloid oligomers. Methods: The effect of monomeric, oligomeric and fibrillar A , -synuclein, prion, Huntington’s polyQ and amylin (IAPP) were assessed on 1) CaN activity, CREB-mediated transcription and CaN-dependent cell death in human SY5Y neuroblastoma cells; 2) CaN-dependent long term potentiation (LTP) in hippocampal slices and 3) CaN-dependent cognitive function after icv injection in mice. Results: We found that all oligomeric amyloids tested induced CaN and evoked CaN-dependent cell death, whereas their monomeric and fibrillar counterparts were ineffective. We also found that oligomeric A , -synuclein and prion decreased CREBdriven transcription, an event important for LTP and negatively regulated by CaN. Indeed, we found CaN activity to be increased and LTP to be depressed by oligomeric A and -synuclein and this effect was prevented by inhibition of CaN. Lastly, oligomeric A and -synuclein similarly induced CaN and CaN-dependent memory deficits when acutely injected icv in mice. Conclusions: Collectively, these results suggest that there may be a dysfunctional signaling pathway commonly elicited by oligomeric amyloid proteins that involves CaN hyper-activity and produces decreased LTP, memory impairments and eventually cell death, all events playing a central role in such amyloid diseases as AD, PD and Creutzfeldt-Jacob disease. These results further suggest that inhibition of CNS CaN shall be considered as a possible pharmacological target for the treatment of cognitive deficits and neurodegeneration in amyloid diseases.