Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders.

There is increasing appreciation that non-neuronal cells contribute to the initiation, progression and pathology of diverse neurodegenerative disorders. This Review focuses on the role of astrocytes in disorders including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. The important roles astrocytes have in supporting neuronal function in the healthy brain are considered, along with studies that have demonstrated how the physiological properties of astrocytes are altered in neurodegenerative disorders and may explain their contribution to neurodegeneration. Further, the question of whether in neurodegenerative disorders with specific genetic mutations these mutations directly impact on astrocyte function, and may suggest a driving role for astrocytes in disease initiation, is discussed. A summary of how astrocyte transcriptomic and proteomic signatures are altered during the progression of neurodegenerative disorders and may relate to functional changes is provided. Given the central role of astrocytes in neurodegenerative disorders, potential strategies to target these cells for future therapeutic avenues are discussed.

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

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-ß 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-ß-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-ß 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-ß 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.

TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-ß peptide.

BACKGROUND: Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease (AD). However, the key mechanisms that maintain plasticity of synapses during adulthood or initiate synapse dysfunction in AD remain unknown. Recent studies suggest that astrocytes contribute to functional changes observed during synaptic plasticity and play a major role in synaptic dysfunction but astrocytes behavior and involvement in early phases of AD remained largely undefined. METHODS: We measure astrocytic calcium activity in mouse CA1 hippocampus stratum radiatum in both the global astrocytic population and at a single cell level, focusing in the highly compartmentalized astrocytic arbor. Concurrently, we measure excitatory post-synaptic currents in nearby pyramidal neurons. RESULTS: We find that application of soluble Aß oligomers (Aßo) induced fast and widespread calcium hyperactivity in the astrocytic population and in the microdomains of the astrocyte arbor. We show that astrocyte hyperactivity is independent of neuronal activity and is repaired by transient receptor potential A1 (TRPA1) channels blockade. In return, this TRPA1 channels-dependent hyperactivity influences neighboring CA1 neurons triggering an increase in glutamatergic spontaneous activity. Interestingly, in an AD mouse model (APP/PS1-21 mouse), astrocyte calcium hyperactivity equally takes place at the beginning of Aß production, depends on TRPA1 channels and is linked to CA1 neurons hyperactivity. CONCLUSIONS: Our experiments demonstrate that astrocytes contribute to early Aßo toxicity exhibiting a global and local Ca2+ hyperactivity that involves TRPA1 channels and is related to neuronal hyperactivity. Together, our data suggest that astrocyte is a frontline target of Aßo and highlight a novel mechanism for the understanding of early synaptic dysregulation induced by soluble Aßo species.