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. 2020 Mar;19(3):e13113.
doi: 10.1111/acel.13113. Epub 2020 Feb 14.

TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer's disease

Yehong Du  1 , Min Fu  1 , Zhilin Huang  1 , Xin Tian  2 , Junjie Li  1 , Yayan Pang  1 , Weihong Song  1   3 , Yu Tian Wang  1   4 , Zhifang Dong  1
Affiliations

TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer's disease

Yehong Du et al. Aging Cell. 2020 Mar.

Abstract

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. The accumulation of amyloid-β (Aβ) peptides is one of the pathological hallmarks of AD and leads to the impairments of synaptic plasticity and cognitive function. The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is involved in synaptic plasticity and memory. However, the role of TRPV1 in AD pathogenesis remains largely elusive. Here, we reported that the expression of TRPV1 was decreased in the brain of APP23/PS45 double transgenic AD model mice. Genetic upregulation of TRPV1 by adeno-associated virus (AAV) inhibited the APP processing and Aβ deposition in AD model mice. Meanwhile, upregulation of TRPV1 ameliorated the deficits of hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory through inhibiting GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis. Furthermore, pharmacological activation of TRPV1 by capsaicin (1 mg/kg, i.p.), an agonist of TRPV1, dramatically reversed the impairments of hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, these results indicate that TRPV1 activation effectively ameliorates cognitive and synaptic functions through inhibiting AMPAR endocytosis in AD model mice and could be a novel molecule for AD treatment.

Keywords: AMPA receptor endocytosis; Alzheimer's disease; TRPV1; capsaicin; learning and memory; long-term potentiation.

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Conflict of interest statement

The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1
TRPV1 decreases APP processing in APP23/PS45 mice. (a) The protein level of TRPV1 in the brains of WT and APP23/PS45 mice at the age of 4 months. t = 40.605, p < .001 by unpaired Student's t test. n = 6 in each group. (b–h) The relative protein levels of TRPV1 (b and c), APP (b and d), c99 (b and e), c89 (b and f), BACE1 (b and g), and PS1 (b and h) are normalized by WT (n = 4–9 in each group). One‐way ANOVA: F (3,17) = 28.993, p < .001 for TRPV1; F (3,29) = 13.818, p < .001 for APP; F (3,13) = 27.499, p < .001 for c99; F (3,13) =7.871, p = .004 for c89; F (3,17) =14.975, p < .001 for BACE1; and F (3,25) = 4.488, p = .012 for PS1. (i and j) The number of neuritic plaques detected by immunohistochemistry in the hippocampus of APP23/PS45 mice (n = 14–42 slices from 3–9 mice in each group). One‐way ANOVA: F (3,122) = 15.092, p < .001. Data are expressed as mean ± SEM, *p < .05, **p < .01, ***p < .001
Figure 2
Figure 2
TRPV1 rescues the impairment of LTP in the CA1 area of hippocampus in APP23/PS45 mice. Representative fEPSP traces (a) and plots of the normalized slopes (b) of the fEPSP 5 min before and 55 min after TBS delivery. (c) Bar graphs of the average percentage changes in the fEPSP slope 55–60 min after TBS delivery (n = 5–6 slices from 4–6 mice in each group). One‐way ANOVA: F (3,19) = 7.330, p = .002. Data are expressed as means ± SEM, *p < .05, ***p < .001
Figure 3
Figure 3
TRPV1 increases the expression of GluA2 in the synapse. The relative protein levels of total GluA1 (a), total GluA2 (b), synaptic GluA1(c), and synaptic GluA2 (d) are normalized by WT mice (n = 4–6 in each group). One‐way ANOVA: F (3,21) = 0.707, p = .559 for total GluA1; F (3,13) = 0.351, p = .789 for total GluA2; F (3,21) = 0.636, p = .601 for synaptic GluA1; and F (3,13) = 10.829, p = .001 for synaptic GluA2. Data are expressed as mean ± SEM, *p < .05
Figure 4
Figure 4
TRPV1 interacts with GluA2 subunit of AMPAR. (a and b) Immunoprecipitation (IP) of hippocampal samples from WT and APP23/PS45 mice after extraction in lysis buffer with antibodies to TRPV1 or negative control antibodies (IgG) and immunoblot analysis with the indicated antibodies to the TRPV1, GluA1 (a), and GluA2 (b). (c and d) IP of hippocampal samples from WT and APP23/PS45 mice after extraction in lysis buffer with antibodies to GluA1, GluA2, or IgG and immunoblot analysis with the indicated antibodies to the TRPV1, GluA1 (c), and GluA2 (d)
Figure 5
Figure 5
Genetic upregulation of TRPV1 rescues learning and memory deficits in APP23/PS45 mice. (a) The escape latency to the hidden platform during spatial learning in the Morris water maze paradigm (n = 16–24 in each group). Repeated measures ANOVA: F (3,74) = 9.748, p < .001. (b) The number of entries into the platform zone. One‐way ANOVA: F (3,74) = 3.281, p = .026. (c) The latency to the escape box during spatial learning in the Barnes maze paradigm (n = 8–9 in each group). Repeated measures ANOVA: F (3,41) = 20.139, p < .001. (d) The occurrence of head dips to the escape hole during memory retrieval. One‐way ANOVA: F (3,41) = 10.793, p < .001. Data are expressed as mean ± SEM, *p < .05, **p < .01, ***p < .001
Figure 6
Figure 6
Capsaicin rescues learning and memory deficits in APP23/PS45 mice. (a) The escape latency to the hidden platform during spatial learning in the Morris water maze paradigm (n = 7–10 in each group). Repeated measures ANOVA: F (5,42) = 6.274, p < .001. (b) The number of entries into the platform zone. One‐way ANOVA: F (5,42) = 4.276, p = .003. (c) The latency to the escape box during spatial learning in the Barnes maze paradigm (n = 5–8 in each group). Repeated measures ANOVA: F (5,37) = 8.805, p < .001. (d) The occurrence of head dips to the escape hole during memory retrieval. One‐way ANOVA: F (5,37) = 5.024, p = .001. Data are expressed as mean ± SEM, *p < .05, **p < .01
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References

    1. Abdelhamid, R. E. , Kovacs, K. J. , Nunez, M. G. , & Larson, A. A. (2014). Depressive behavior in the forced swim test can be induced by TRPV1 receptor activity and is dependent on NMDA receptors. Pharmacological Research, 79, 21–27. 10.1016/j.phrs.2013.10.006 - DOI - PMC - PubMed
    1. Beyreuther, K. , & Masters, C. L. (1991). Amyloid precursor protein (APP) and beta A4 amyloid in the etiology of Alzheimer's disease: Precursor‐product relationships in the derangement of neuronal function. Brain Pathology, 1(4), 241–251. - PubMed
    1. Bliss, T. V. , & Collingridge, G. L. (1993). A synaptic model of memory: Long‐term potentiation in the hippocampus. Nature, 361(6407), 31–39. 10.1038/361031a0 - DOI - PubMed
    1. Chen, L. , Huang, Z. , Du, Y. , Fu, M. , Han, H. , Wang, Y. , & Dong, Z. (2017). Capsaicin attenuates amyloid‐beta‐induced synapse loss and cognitive impairments in mice. Journal of Alzheimer's Disease, 59(2), 683–694. 10.3233/JAD-170337 - DOI - PubMed
    1. Cho, H. J. , Jin, S. M. , Youn, H. D. , Huh, K. , & Mook‐Jung, I. (2008). Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling. Aging Cell, 7(2), 137–147. 10.1111/j.1474-9726.2007.00360.x - DOI - PubMed

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