AbstractBackgroundThe 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 such 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 brought by an early chronic pharmacological inhibition of TRPA1 channel on Alzheimer’s disease progression.MethodsWe administered a specific inhibitor of TRPA1 channel (HC030031) intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer’s disease. We characterized short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade on Alzheimer’s disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels.ResultsOur 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, preserves structural synaptic integrity and strengthens the glial plaque barrier. These protective effects preserved spatial working-memory in this Alzheimer’s disease mouse model.ConclusionThe toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer’s disease progression. TRPA1 blockade prevent irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.
Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
