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

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.

Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice

“…Our present findings further support the protective effects of chili consumption on cognition. In previous studies, it has been reported that capsaicin could improve cognitive performance in wild-type mice or rats but with controversy 45,48,49 , all studies did not find obvious adverse effects of capsaicin administration. Further studies are required to make clear whether capsaicin can enhance memory in wild-type animals or healthy humans.…”

“…TRPV1 is known as capsaicin receptor. Recent studies has reported that genetic upregulation of TRPV1 attenuated Aβ burden in brain of AD model mice and rescued memory decline and Aβ-induced neuronal function and network impairment in vivo and in vitro 44,45 , although controversial report exists 46 . In our present study, we did not detected significant differences in TRPV1 expression between mice received capsaicin-rich diet and those received standard diet.…”

Spicy food consumption is associated with cognition and cerebrospinal fluid biomarkers of Alzheimer disease

“…Moreover, recent animal studies from our and other groups suggested that consumption of capsaicin was able to reduce brain Aβ pathology, attenuate neurodegeneration, and improve cognition in AD transgenic animals. [ 14 , 15 ] Taken together, our findings suggest that a capsaicin-rich diet not only offers protection against cognitive decline but also may modify AD-type pathologies in the brain. However, a recent study suggested that higher spicy food intake was associated with worse memory decline in an open cohort study in China.…”

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

“…An increase in surface AMPARs through exocytosis leads to the expression of long-term potentiation (LTP), whereas internalization of AMPARs causes long-term depression (LTD) ( Chidambaram et al., 2019 ; Collingridge et al., 2004 ; Derkach et al., 2007 ; Ju and Zhou, 2018 ; Kopec et al., 2006 ; Lledo et al., 1998 ; Lüscher et al., 1999 ; Makino and Malinow, 2009 ; Malinow and Malenka, 2002 ; Shepherd and Huganir, 2007 ; Song and Huganir, 2002 ). Consistent with impairments in synaptic function, a reduction in AMPARs has been observed in the brains of both human patients with AD and mouse models of AD ( Armstrong et al., 1994 ; Cantanelli et al., 2014 ; Carter et al., 2004 ; Chang et al., 2006 ; D'Amelio et al., 2011 ; Dewar et al., 1991 ; Du et al., 2020 ; Gao et al., 2016 ; Gong et al., 2009 ; Jacob et al., 2007 ; Monteiro-Fernandes et al., 2020 ; Samra and Ramtahal, 2012 ; Thorns et al., 1997 ; Wakabayashi et al., 1999 ; Yasuda et al., 1995 ). In line with this, incubation of neurons with Aβ results in down-regulation in AMPAR amounts ( Guntupalli et al., 2016 ; Miyamoto et al., 2016 ; Parameshwaran et al., 2008 ; Thomas et al., 2017 ; Wisniewski et al., 2011 ; Yu and Lu, 2012 ; Zhang et al., 2018 ).…”