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

Review of Alzheimer’s disease drugs and their relationship with neuron-glia interaction

“…Through the use of widefield calcium imaging of neurons and resting-state functional magnetic resonance imaging (rsfMRI), Shah et al recently discovered the importance of astrocytes in maintaining large-scale networks in the healthy brain. They also showed their involvement in early functional connectivity disruptions in AD ( Shah et al, 2022 ). They explained the elevated calcium signals in the astrocytes of AD models as being caused by increased astrocyte reactivity in response to plaques, which led to hyperactivity of astrocytic calcium, altered purinergic receptor regulation, increased calcium efflux from mitochondria by reactive oxygen species production, and aberrant ATP release ( Shah et al, 2022 ).…”

“…They also showed their involvement in early functional connectivity disruptions in AD ( Shah et al, 2022 ). They explained the elevated calcium signals in the astrocytes of AD models as being caused by increased astrocyte reactivity in response to plaques, which led to hyperactivity of astrocytic calcium, altered purinergic receptor regulation, increased calcium efflux from mitochondria by reactive oxygen species production, and aberrant ATP release ( Shah et al, 2022 ). Long before amyloid plaques were present, they discovered decreased in vivo calcium signaling in astrocytes.…”

Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments

“…These effects were found to involve a proapoptotic mechanism, dependent on glycogen synthase kinase-3β (GSK3β) activation (a kinase involved in tau hyperphosphorylation), and a proinflammatory response. Similarly, decreased calcium signaling and reduced IP3 receptor type 2 (IP3R2) expression in astrocytes was reported in human brains from individuals with AD, and associated with early alterations of functional connectivity and network activity in the APPNL-F mice model for AD [ 45 ]. In the same study, neuronal hyperactivity, seizure susceptibility, behavioral disruptions and abnormal functional connectivity were corrected when astrocytes returned to normal calcium signaling.…”

Mitochondrial Ca2+ Signaling and Bioenergetics in Alzheimer’s Disease

“…Conversely, APP NL-F mice showed decreased astrocyte Ca 2+ activity correlated with neuronal hyperactivity in the early phase of the disease. Interestingly, the rescue of astrocyte Ca 2+ activity through chemogenetic tools is also able to recover neuronal deficits [ 127 ]. An attenuated cytosolic Ca 2+ activity in response to locomotion has also been reported in the astrocyte of tg-ArcSwe mice with overt Aβ plaque deposition [ 128 ].…”