Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s Disease

Abstract

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex, several years before amyloid deposition. We found the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astroglial calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral hyperactivity. In conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease

“…In addition, females were found to show higher transcriptional susceptibility to AD pathology, suggesting a gender-based astrocyte disease response (Mathys et al, 2019). Contrary to what was recently observed for the pre-symptomatic AD stage (Shah et al, 2022), Ca 2+ signalling appears increased in astrocytes at late disease stages (6-9 months old) in the APPSwe/PS1dE9 mouse model (Kuchibhotla et al, 2009;Lines et al, 2022), and this has been linked to increased astrocyte reactivity (Shigetomi et al, 2019). Increased Ca 2+ signalling typically enhances the release of gliotransmitters, such as glutamate (Perea et al, 2009).…”

“…hM3Dqmediated astrocyte activation rescued astrocytic Ca 2+ signalling in the cingulate cortex of pre-symptomatic App NL-G-F mice and, consequently, neuronal activity and functional connectivity of brain circuits. This also prevented typical symptoms presenting at the early stages of AD, like seizures and day/night hyperactivity, emphasizing that astrocytes are likely major players in early AD (Figure 2) (Shah et al, 2022). On the other hand, when, in the same study, astrocytes from control animals were similarly activated through hM3Dq, the increase in Ca 2+ signalling was much more pronounced and induced neuronal hyperactivity (Shah et al, 2022).…”

“…In the APPSwe/PS1dE9 mouse model, astrocytes display altered expression of genes associated with synaptic regulation from 4 months onward (Pan et al, 2020). In fact, a recent study by Shah and colleagues demonstrated decreased astrocytic Ca 2+ signalling in the cingulate cortex of App NL-G-F mice aged 6-12 weeks, reflecting disrupted network activity in this brain area before any detectable Aβ plaque formation, just as in human AD patients (Shah et al, 2022). At the later stages of AD, reactive astrocytes emerge and secrete IL-1β, and TNF-α, among other pro-inflammatory cytokines (Osborn et al, 2016).…”

Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer’s disease?

“…Accumulation of astrocytes, indeed, has been detected in proximity of the Aβ deposits in AD patients (Kuchibhotla et al, 2009). Recently, it has been shown that the functional connectivity of astrocytes is altered early in AD (Shah et al, 2022). Indeed, it is observed a decreased calcium signaling in astrocytes of AD mice before the appearance of Aβ plaques (Shah et al, 2022).…”

“…Recently, it has been shown that the functional connectivity of astrocytes is altered early in AD (Shah et al, 2022). Indeed, it is observed a decreased calcium signaling in astrocytes of AD mice before the appearance of Aβ plaques (Shah et al, 2022). Moreover, disruption of astrocyte network in AD affects the cortical neuronal activity, promoting cognitive decline (Lines et al, 2022).…”