Journal
JOURNAL OF NEUROINFLAMMATION
Volume 13, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s12974-016-0557-z
Keywords
Transient receptor potential ankyrin 1; Calcium; Alzheimer's disease; Inflammation; Protein phosphatase 2B
Categories
Funding
- Ministry of Science and Technology [MOST-102-2628-B-010-001-MY3, MOST-103-2628-B-010-040-MY3, MOST-104-2320-B-010-041-MY3]
- Yen Tjing Ling Medical Foundation [CI-104-10, CI-104-13]
- Ministry of Education, Aim for the Top University Plan, Taiwan
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Background: Transient receptor potential ankyrin 1 (TRPA1) channel plays an important role in pain and inflammation. However, little is known about the significance of the TRPA1 channel in the pathophysiology of Alzheimer's disease (AD). Methods: Wild-type (WT), TRPA1(-/-), amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) mice, the mouse model of AD, and APP/PS1 Tg/TRPA1(-/-) mice were used to examine the role of TRPA1 in pathogenesis of AD. Western blot was used for protein expression; immunohistochemistry was used for histological examination. The mouse behaviors were evaluated by locomotion, nesting building, Y-maze and Morris water maze tests; levels of interleukin (IL)-1 beta, IL-4, IL-6 and IL-10 and the activities of protein phosphatase 2B (PP2B), NF-kappa B and nuclear factor of activated T cells (NFAT) were measured by conventional assay kits; Fluo-8 NW calcium (Ca2+) assay kit was used for the measurement of intracellular Ca2+ level in primary astrocytes and HEK293 cells. Results: The protein expression of TRPA1 channels was higher in brains, mainly astrocytes of the hippocampus, from APP/PS1 Tg mice than WT mice. Ablation of TRPA1-channel function in APP/PS1 Tg mice alleviated behavioral dysfunction, A beta plaque deposition and pro-inflammatory cytokine production but increased astrogliosis in brain lesions. TRPA1 channels were activated and Ca2+ influx was elicited in both astrocytes and TRPA1-transfected HEK293 cells treated with fibrilized A beta(1-42); these were abrogated by pharmacological inhibition of TRPA1 channel activity, disruption of TRPA1 channel function or removal of extracellular Ca2+. Inhibition of TRPA1 channel activity exacerbated A beta(1-42)-induced astrogliosis but inhibited A beta(1-42)-increased PP2B activation, the production of pro-inflammatory cytokines and activities of transcriptional factors NF-kappa B and NFAT in astrocytes and in APP/PS1 Tg mice. Pharmacological inhibition of PP2B activity diminished the fibrilized A beta(1-42)-induced production of pro-inflammatory cytokines, activation of NF-kappa B and NFAT and astrogliosis in astrocytes. Conclusions: TRPA1-Ca2+-PP2B signaling may play a crucial role in regulating astrocyte-derived inflammation and pathogenesis of AD.
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