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The Journal of Neuroscience, November 8, 2006, 26(45):11652-11664; doi:10.1523/JNEUROSCI.2490-06.2006

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Neurobiology of Disease
Broad-Spectrum Effects of 4-Aminopyridine to Modulate Amyloid _1–42-Induced Cell Signaling and Functional Responses in Human Microglia

Sonia Franciosi,¹ Jae K. Ryu,¹ Hyun B. Choi,^1,2 Lesley Radov,⁴ Seung U. Kim,^2,3 and James G. McLarnon¹

¹Departments of Anesthesiology, Pharmacology, and Therapeutics and ²Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, ³Brain Disease Research Center, Ajou University, Suwon 443-749, Korea, and ⁴Astra Zeneca CNS Discovery, Wilmington, Delaware 19850

Correspondence should be addressed to Dr. James G. McLarnon, Departments of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Email: mclarnon{at}interchange.ubc.ca

We investigated the modulating actions of the nonselective K⁺ channel blocker 4-aminopyridine (4-AP) on amyloid (A_1–42)-induced human microglial signaling pathways and functional processes. Whole-cell patch-clamp studies showed acute application of A_1–42 (5 µM) to human microglia led to rapid expression of a 4-AP-sensitive, non-inactivating outwardly rectifying K⁺ current (I_K). Intracellular application of the nonhydrolyzable analog of GTP, GTPS, induced an outward K⁺ current with similar properties to the A_1–42-induced I_K including sensitivity to 4-AP (IC₅₀ = 5 mM). Reverse transcriptase-PCR showed a rapid expression of a delayed rectifier Kv3.1 channel in A_1–42-treated microglia. A_1–42 peptide also caused a slow, progressive increase in levels of [Ca²⁺]_i (intracellular calcium) that was partially blocked by 4-AP. Chronic exposure of human microglia to A_1–42 led to enhanced p38 mitogen-activated protein kinase and nuclear factor B expression with factors inhibited by 4-AP. A_1–42 also induced the expression and production of the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-, the chemokine IL-8, and the enzyme cyclooxygenase-2; 4-AP was effective in reducing all of these pro-inflammatory mediators. Additionally, toxicity of supernatant from A_1–42-treated microglia on cultured rat hippocampal neurons was reduced if 4-AP was included with peptide. In vivo, injection of A_1–42 into rat hippocampus induced neuronal damage and increased microglial activation. Daily administration of 1 mg/kg 4-AP was found to suppress microglial activation and exhibited neuroprotection. The overall results suggest that 4-AP modulation of an A_1–42-induced I_K (candidate channel Kv3.1) and intracellular signaling pathways in human microglia could serve as a therapeutic strategy for neuroprotection in Alzheimer's disease pathology.

Key words: Alzheimer's disease; amyloid peptide; 4-aminopyridine; microglia; inflammation; cytokines

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Received June 13, 2006; revised Sept. 21, 2006; accepted Sept. 27, 2006.

Correspondence should be addressed to Dr. James G. McLarnon, Departments of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Email: mclarnon{at}interchange.ubc.ca

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