Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-β and tau in a mouse model of Alzheimer’s disease

Dec 10, 2019Human molecular genetics

Removing a calcium-sensitive pain receptor improves memory and lowers Alzheimer's-related proteins in mice

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Abstract

TRPV1 deficiency is associated with improved memory function and reduced levels of amyloid-β and tau in a mouse model of Alzheimer's disease.

TRPV1 is a pain receptor linked to anxiety and depression behaviors.
Loss of TRPV1 functionality increases expression of genes related to brain plasticity and cell growth.
In a mouse model, TRPV1+/+ mice exhibited memory impairment and increased hippocampal Ca2+, amyloid-β, and tau levels.
TRPV1-/- mice showed better memory function and lower levels of hippocampal Ca2+, amyloid-β, and tau compared to TRPV1+/+ mice.
Using specific inhibitors decreased the production of amyloid-β and tau in neuron cultures derived from the mouse model.

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The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer's disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/-) and knockout (TRPV1-/-) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals' memory function, hippocampal Ca2+ levels and amyloid-β (Aβ) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD-/-/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aβ and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1-/- mice had better memory function and lower levels of hippocampal Ca2+, Aβ, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aβ, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.

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Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-β and tau in a mouse model of Alzheimer’s disease

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