Role of transient receptor potential ankyrin 1 channels in Alzheimer's disease.
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)-1β, IL-4, IL-6 and IL-10 and the activities of protein phosphatase 2B (PP2B), NF-κB and nuclear factor of activated T cells (NFAT) were measured by conventional assay kits; Fluo-8 NW calcium (Ca(2+)) assay kit was used for the measurement of intracellular Ca(2+) 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, Aβ plaque deposition and pro-inflammatory cytokine production but increased astrogliosis in brain lesions. TRPA1 channels were activated and Ca(2+) influx was elicited in both astrocytes and TRPA1-transfected HEK293 cells treated with fibrilized Aβ1-42; these were abrogated by pharmacological inhibition of TRPA1 channel activity, disruption of TRPA1 channel function or removal of extracellular Ca(2+). Inhibition of TRPA1 channel activity exacerbated Aβ1-42-induced astrogliosis but inhibited Aβ1-42-increased PP2B activation, the production of pro-inflammatory cytokines and activities of transcriptional factors NF-κB and NFAT in astrocytes and in APP/PS1 Tg mice. Pharmacological inhibition of PP2B activity diminished the fibrilized Aβ1-42-induced production of pro-inflammatory cytokines, activation of NF-κB and NFAT and astrogliosis in astrocytes.


CONCLUSIONS
TRPA1 - Ca(2+) - PP2B signaling may play a crucial role in regulating astrocyte-derived inflammation and pathogenesis of AD.
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Kuan-I
KI
Lee
Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan.
Hsueh-Te
HT
Lee
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Hui-Ching
HC
Lin
Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan.
Huey-Jen
HJ
Tsay
Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan.|International Graduate Program, Interdisciplinary Neuroscience Program, Taipei, Taiwan.
Feng-Chuan
FC
Tsai
Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Song-Kun
SK
Shyue
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. tslee@ym.edu.tw.|Genome Research Center, National Yang-Ming University, Taipei, Taiwan. tslee@ym.edu.tw.
Tzong-Shyuan
TS
Lee
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse
Alzheimer’s disease; Calcium; Inflammation; Protein phosphatase 2B; Transient receptor potential ankyrin 1