Abstract
Background 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 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.
Methods We 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.
Results 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, preserves structural synaptic integrity and strengthens the glial plaque barrier. These protective effects preserved spatial working-memory in this Alzheimer’s disease mouse model.
Conclusion The 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Abbreviations Aβ: Amyloid-β peptide; Aβo: Amyloid-β oligomers; aMCI: amnestic Mild Cognitive Impairment; APP: Amyloid Precursor Protein; Ca: Calcium; CA1: Cornu Ammonis 1; CNS: Central Nervous System; GFAP: Glial Fibrillary Acidic Protein; Iba1: Ionized calcium-binding adaptor molecule 1; P2YR: P2Y purinoreceptor; PS1: Presenilin 1; DAAO: R. gracilis D-amino acid oxidase; ROI: Region Of Interest; sEPSC: spontaneous Excitatory Post-Synaptic Current; SIC: Slow Inward Current; TRPA1: Transient Receptor Potential A1 channel; TTX: tetrodotoxin; WT: Wild-Type