Astrocyte–neuron interplay is critical for Alzheimer's disease pathogenesis and is rescued by TRPA1 channel blockade
- 24 July 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 145 (1), 388-405
- https://doi.org/10.1093/brain/awab281
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 the 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.Keywords
Funding Information
- INSERM, University Grenoble Alpes, France Alzheimer and the French National Research Agency (ANR-15-IDEX-02)
This publication has 63 references indexed in Scilit:
- Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s diseaseProceedings of the National Academy of Sciences of the United States of America, 2012
- Reduction of Hippocampal Hyperactivity Improves Cognition in Amnestic Mild Cognitive ImpairmentNeuron, 2012
- Neuropathological Alterations in Alzheimer DiseaseCold Spring Harbor Perspectives in Medicine, 2011
- High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive ImpairmentNeuroImage, 2010
- Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networksNature Neuroscience, 2010
- Long-term potentiation depends on release of d-serine from astrocytesNature, 2010
- Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer MiceScience, 2009
- Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive declineJournal of Neurology, Neurosurgery & Psychiatry, 2007
- TRPA1 mediates formalin-induced painProceedings of the National Academy of Sciences of the United States of America, 2007
- Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathologyEMBO Reports, 2006