Albrieux, M. | Search bioRxiv

bioRxiv2021

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

BackgroundThe sequence of cellular dysfunctions in preclinical Alzheimers 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 Alzheimers disease in both humans and mouse models. The most common hypothesis describes amyloid {beta} 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 {beta}-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 Alzheimers disease progression. MethodsWe administered a specific inhibitor of TRPA1 channel (HC030031) intraperitoneally from the onset of amyloid {beta} overproduction in the APP/PS1-21 mouse model of Alzheimers disease. We characterized short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade on Alzheimers disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels. ResultsOur results revealed that the first observable disruptions in the Alzheimers 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 Alzheimers disease mouse model. ConclusionThe toxic effect of amyloid {beta} on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimers disease progression. TRPA1 blockade prevent irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.

neuroscience↗

bioRxiv2020

Neuron-gated silicon nanowire field effect transistors to follow single spike propagation within neuronal network

Silicon nanowire field effect transistors SiNW-FETs provide a local probe for sensing neuronal activity at the subcellular scale, thanks to their nanometer size and ultrahigh sensitivity. The combination with micro-patterning or microfluidic techniques to build model neurons networks above SiNW arrays could allow monitoring spike propagation and tailor specific stimulations, being useful to investigate network communications at multiple scales, such as plasticity or computing processes. This versatile device could be useful in many research areas, including diagnosis, prosthesis, and health security. Using top-down silicon nanowires-based array, we show here the ability to record electrical signals from matured neurons with top-down silicon nanowires, such as local field potential and unitary spike within ex-vivo preparations and hippocampal neurons grown on chip respectively. Furthermore, we demonstrate the ability to guide neurites above the sensors array during 3 weeks of cultures and follow propagation of spikes along cells. Silicon nanowire field effect transistors are obtained by top-down approach with CMOS compatible technology, showing the possibility to implement them at manufacturing level. These results confirm further the potentiality of the approach to follow spike propagation over large distances and at precise location along neuronal cells, by providing a multiscale addressing at the nano and mesoscales.

bioengineering↗