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The present study examined the effect of indomethacin (IM), a cyclooxygenase inhibitor, on learning and memory functions. IM activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) in cultured rat hippocampal neurons. IM (100 µM) significantly increased the rate of spontaneous AMPA receptor-mediated miniature excitatory postsynaptic currents elicited from CA1 pyramidal neurons of rat hippocampal slices, without affecting the amplitude, and enhanced extracellular high K+ (20 mM)-induced glutamate release from rat hippocampal slices, indicating that IM stimulates presynaptic glutamate release. Those IM effects were clearly inhibited by the CaMKII inhibitor KN-93. IM persistently facilitated synaptic transmission monitored from the CA1 region of rat hippocampal slices in a concentration (1-100 µM)-dependent manner that was also abolished by KN-93. In the water maze test, IM (1 mg/kg, i.p.) enhanced spatial learning and memory ability for normal rats, and ameliorated scopolamine-induced spatial learning and memory impairment or age-related spatial learning and memory deterioration for senescence-accelerated mouse-prone 8 mice. In the test to learn 15 numbers consisting of three patterns of five digit number for healthy human subjects, oral intake with IM (25 mg/kg) significantly raised the scores of correct number arrangements that subjects memorized 5 min and 3 days after the test. The results of the present study indicate that IM could enhance learning and memory potential by facilitating hippocampal synaptic transmission as a result from stimulating presynaptic glutamate release under the control of CaMKII. J. Cell. Physiol. 227: 919-926, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) by inhibiting protein phosphatase-1 (PP-1). DCP-LA induced a transient huge facilitation of synaptic transmission monitored from the CA1 region of rat hippocampal slices, which was largely inhibited by the CaMKII inhibitor KN-93. DCP-LA potentiated kainate-evoked whole-cell membrane currents for Xenopus oocytes expressing α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors composed of the GluR1, GluR3, GluR1/GluR2, GluR1/GluR3, and GluR1/GluR2/GluR3 subunits, and the potentiation was significantly inhibited by KN-93. A similar potentiation was still found with mutant GluR1 (S831A) receptor lacking CaMKII phosphorylation site. The GluR1 and GluR2 subunits formed AMPA receptors in the rat hippocampus, and DCP-LA increased expression of both the subunits on the plasma membrane. The DCP-LA action was blocked by KN-93 and the exocytosis inhibitor botulinum toxin type A, but not by the endocytosis inhibitor phenylarsine oxide. DCP-LA, thus, appears to activate CaMKII through PP-1 inhibition, that stimulates AMPA receptor exocytosis to increase expression of the receptors on the plasma membrane, responsible for potentiate AMPA receptor responses and facilitation of hippocampal synaptic transmission. J. Cell. Physiol. 221: 183–188, 2009. © 2009 Wiley-Liss, Inc [ABSTRACT FROM AUTHOR]

Objective Soluble oligomers of amyloid β (Aβ), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein ( APP) mutation that may provide evidence to address this question. Methods A Japanese pedigree showing Alzheimer's-type dementia was examined for mutations in APP, PSEN1, and PSEN2. In addition, 5,310 Japanese people, including 2,121 patients with AD, were screened for the novel APP mutation. The pathogenic effects of this mutation on Aβ production, degradation, aggregation, and synaptotoxicity were also investigated. Results We identified a novel APP mutation (E693Δ) producing variant Aβ lacking gulutamate-22 (E22Δ) in Japanese pedigrees showing Alzheimer's-type dementia and AD. Although the secretion of total Aβ was markedly reduced by this mutation, the variant Aβ was more resistant to proteolytic degradation. The mutant peptides showed the unique aggregation property of enhanced oligomerization but no fibrillization, and inhibited hippocampal long-term potentiation more potently than wild-type peptide in rats in vivo. Consistent with the nonfibrillogenic property of the variant Aβ, a very low amyloid signal was observed in the patient's brain on positron emission tomography using Pittsburgh compound-B. Interpretation The E693Δ mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Aβ oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Aβ oligomers. Ann Neurol 2008 [ABSTRACT FROM AUTHOR]

Background: In our earlier study, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis-double bonds, facilitated hippocampal synaptic transmission by stimulating glutamate release from presynaptic terminals as mediated via α7 acetylcholine (Ach) receptors under the influence of protein kinase C. The present study assessed the possibility of using DCP-LA as a cognitive enhancer in animal models. Methods: Amyloid-β1−40 peptide (300 pM/day) or saline was continuously injected in the right lateral ventricle of rats for 2 weeks. Then, the water maze test was carried out, once per day for 7 days, 1 h after the intraperitoneal injection with DCP-LA or saline. In a different set of experiments, rats were intraperitoneally injected with scopolamine (1 mg/kg) and the water maze test was performed twice per day, with the first test taking place 1 h after the intraperitoneal injection with DCP-LA, galantamine or saline, and the second test starting 2 min after the end of the first. Results: Continuous intraventricular injection with amyloid-β1−40 peptide in the rat lateral ventricle prolonged the latency for acquisition in the water maze test. DCP-LA (1 mg/kg, intraperitoneal (i.p.)) significantly improved the impairment, which reached a level similar to the latency for sham. Furthermore, DCP-LA (1 mg/kg, i.p.) significantly ameliorated learning and memory deficits in rats treated with scopolamine and was, if not more, effective than galantamine, a modest inhibitor of acetylcholinesterase with nicotinic ACh receptor modulation. Conclusion: The results of the present study show that DCP-LA ameliorates learning and memory deficits induced by amyloid-β1−40 peptide or scopolamine. DCP-LA may thus offer new hope for dementia patients. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine (ACh) receptors, such as α7, α3β4 and α4β2 receptors in the hippocampus, are suggested to modulate neurotransmitter release. 8-[2-(2-Pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) (100 n m), a linoleic acid derivative, potentiated responses of α7, α3β4 and α4β2 ACh receptors expressed in Xenopus oocytes that are blocked by 3-(1-[dimethylaminopropyl] indol-3-yl)-4-[indol-3-yl] maleimide (GF109203X), a selective inhibitor of protein kinase C (PKC), except for α3β4 ACh receptors. DCP-LA enhanced the nicotine-triggered release of GABA from rat hippocampal slices in the presence of tetrodotoxin in a bell-shaped dose-dependent manner at concentrations ranging from 10 n m to 10 µ m, although DCP-LA by itself had no effect on GABA release. The DCP-LA action was inhibited by GF109203X or α-bungarotoxin, an inhibitor of α7 ACh receptors, but not by mecamylamine or dihydro-β-erithroidine, an inhibitor of α3β4 and α4β2 ACh receptors. A similar effect on GABA release was obtained with 12- O-tetradecanoylphorbol 13-acetate, a PKC activator. DCP-LA (100 n m) also enhanced GABA release triggered by choline, an agonist of α7 ACh receptors, but not 3-[2(s)-azetidinylmethoxy] pyridine, an agonist of α4β2 ACh receptors. In addition, DCP-LA (100 n m) increased the rate of nicotine-triggered GABAA receptor-mediated miniature inhibitory post-synaptic currents, monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was also inhibited by GF109203X or α-bungarotoxin but not by mecamylamine. Thus, the results of the present study indicate that DCP-LA stimulates GABA release by enhancing activity of pre-synaptic α7 ACh receptors present on the GABAergic terminals of interneurons that transmit to CA1 pyramidal neurons via a PKC pathway. [ABSTRACT FROM AUTHOR]