Astrocyte–neuron interplay is critical for Alzheimer's disease pathogenesis and is rescued by TRPA1 channel blockade

Abstract

The sequence of cellular dysfunctions in preclinical Alzheimer’s disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer’s disease in both humans and mouse models. The most common hypothesis describes amyloid β accumulation as the triggering factor of the disease but the effects of this accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection against Alzheimer’s disease progression provided by early chronic pharmacological inhibition of TRPA1 channel. A specific inhibitor of TRPA1 channel (HC030031) was administered intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer’s disease. Short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade were characterized on Alzheimer’s disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels. Our results revealed that the first observable disruptions in the Alzheimer’s disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction and preserves structural synaptic integrity. These protective effects preserved spatial working-memory in this Alzheimer’s disease mouse model. The toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer’s disease progression. TRPA1 blockade prevents irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.

The Role of Astrocytes in Synapse Loss in Alzheimer's Disease: A Systematic Review

“…In line with this, the expression of transient receptor potential ankyrin 1 (TRPA1), an astrocyte calcium channel, is increased in the hippocampus of 8 months old APP/PS1 mice (Lee et al, 2016 ). Chronic inhibition of TRPA1 in APP/PS1-21 mice that express YFP under control of a axonal promotor showed preserved spine density and morphology (Paumier et al, 2021 ). Overall, these studies show that normalizing astrocytic calcium signaling could prevent synapse loss.…”

“…Other papers analyzed synapse number by performing immunohistochemistry, and subsequently measuring the density or colocalization of synaptic puncta (Li et al, 2016 ; Lin et al, 2018 ; Reichenbach et al, 2018 ; Huang et al, 2019 ). Yet another method is to transfect neurons to induce expression of a fluorescent protein (Talantova et al, 2013 ; Pereira Diniz et al, 2017 ; Paumier et al, 2021 ), stain neurons with a dye (Li et al, 2016 ), or use Golgi staining (Jain et al, 2013 ; Shentu et al, 2019 ) in order to visualize the complete neuronal morphology, which can then be imaged using various microscopes. Electron microscopy is also used to identify and analyze spine density, without the aid of fluorescent staining (Hong et al, 2016 ).…”

A primary rodent triculture model to investigate the role of glia-neuron crosstalk in regulation of neuronal activity

“…Inhibition of astrocytic α2-Na+/K+ adenosine triphosphatase (α2-NKA) in a mouse model of tauopathy suppresses neuroinflammation, and its knockdown halts the progression of tau pathology (Mann et al, 2022). Blocking of the astrocytic calcium channel Transient Receptor Potential Ankyrin 1 (TRPA1) or the enzyme epoxide hydrolase, which is predominantly expressed by astrocytes, have both been shown to normalise astrocytic activity, prevent neuronal dysfunction and improve cognitive function in AD mouse models (Ghosh et al, 2020; Paumier et al, 2022). TREM2 is essential for the transition of homeostatic microglia to a disease-associated state.…”

Astrocytic C–X–C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity

“…It is now established that non-neuronal cells, and particularly astrocytes and microglia, make major contributions to the onset and progression of Alzheimer’s disease [ 61 – 63 ]. We add novel data to this growing body of evidence to demonstrate that interactions between the astrocytic chemokine CXCL1 and its neuronal receptor CXCR2 promote synaptotoxicity in the presence of Aβ.…”