Amyloid β reduces mechanical sensation by attenuating the function of TRPV4 channels in rat small dorsal root ganglion neurons

Abstract

Amyloid β (Aβ) is well known to be a key trigger for the progression of Alzheimer's disease and dementia. Aβ forms oligomers that develop into amyloid plaques, causing neuronal death and dysfunction. Aβ-induced neuronal dysfunction has been reported in peripheral neurons as well as in the brain. We previously reported that transient receptor potential vanilloid 4 (TRPV4) channels play an important role in mechanical sensation in sensory neurons innervating skeletal muscle. However, to date, it remains unclear whether Aβ modulates mechanosensation or TRPV4 channel activity in peripheral sensory neurons. As such, we hypothesized that Aβ acutely impairs the response of small dorsal root ganglion (DRG) neurons to mechanical stimuli by attenuating the function of TRPV4 channels. Purpose: The aim of this investigation was to determine the effects of Aβ1-40 and 1-42 on mechanosensation in small DRG neurons. Method: In in vitro whole-cell patch clamp recordings from cultured rat DRG neurons (Sprague-Dawley rat, n = 4, body weight: 316 ± 57 g), mechanically-activated (MA) current amplitudes or GSK1016790A (a selective agonist of TRPV4, 1 μM)-induced inward currents were measured before and 5 min after application of either HEPES buffered solution (control), Aβ1-40 (2.5 ng/μL), Aβ1-42 (2.5 ng/μL) or Aβ1-40/42 solution (2.5 ng/μL, respectively). Results: MA current amplitude was significantly decreased 5 min after application of both Aβ1-40 (Before vs. After: -71.7 ± 14.5 vs. -13.5 ± 4.8 pA. P < 0.01) and Aβ1-42 (Before vs. After: -63.7 ± 16.2 vs. -14.5 ± 5.9 pA. P < 0.05) while HEPES application did not alter MA currents (Before vs. After: -69.5 ± 17.9 ± -66.2 ± 13.9 pA. P = 0.36). Likewise, GSK1016790A-induced inward current was significantly suppressed by Aβ1-40/42 solution (Fold change in total charge transfer: HEPES vs. Aβ1-40/42: 0.92 ± 0.47 vs. 0.33 ± 0.06. P < 0.05). Conclusion: The data demonstrate that both Aβ1-40 and 1-42 suppress 1) the cellular response to mechanical stimulation and 2) TRPV4 currents in rat small DRG neurons. These findings suggest that both Aβ1-40 and 1-42 attenuate mechanical sensation in DRG neurons by inhibiting TRPV4 channels. Supported by NIH HL-151632 and JSPS 23KJ2207. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.