Astrocytic Calcium and Default Mode Network Dysfunction in Early Stage AD

Evidence suggests that nonneuronal cells, particularly astrocytes, may be a primary site of pathogenesis in early Alzheimer's disease. Functional connectivity changes in the cingulate cortex, a hub of the default mode network, appear years before amyloid plaques and neurofibrillary tangles. Dysfunctional calcium signaling occurs in astrocytes but not neurons, paralleling these connectivity changes; restoring normal calcium reverses them. Astrocytes support bidirectional communication with neurons and coordinate network activity. Studying calcium signaling in default mode network astrocytes could yield insights into early Alzheimer's pathogenesis, integrating findings on connectivity disruption and calcium dysfunction to assess astrocyte influence.

Study at a glance

Abstract

While most theories regarding Alzheimer’s disease (AD) pathogenesis adopt a “neurocentric” perspective, increasing evidence suggests that nonneuronal cells may be a primary site of pathogenesis in early stage AD. Several years prior to the appearance of amyloid plaques and neurofibrillary tangles (NFTs), functional connectivity (FC) changes can be observed in the human cingulate cortex, a principal hub of the default mode network (DMN). Recent studies confirm the presence of dysfunctional calcium signaling in astrocytes, but not neurons, that parallels the observed changes in FC, whereas restoration of normal calcium reverses these changes. Significantly, astrocytes are known to be key elements of brain communication, supporting bidirectional information exchange with neurons at synaptic sites, directly engaging in synaptic transmission, and coordinating multisynaptic activity at circuit and network levels. They are also demonstrably circuit and network-specific. Given their intimate involvement in transmitting neural information, the study of calcium signaling in DMN astrocytes could yield key insights into early AD pathogenesis. Currently, there is a growing body of findings regarding the calcium signaling mechanisms used by astrocytes to initiate or respond to synaptic neural activity and an expanding arsenal of techniques that could provide insight into the systemic consequences of AD-related astrocyte failure. This chapter integrates methods and findings of connectivity disruption in the DMN with those of dysfunctional calcium signaling to provide a perspective on the growing technical synergy that could be used for assessing the influence of astrocytes in early AD pathogenesis.