Fig. 1

Illustration summarizing the hypothesized roles of gliosis and neuroinflammation in AD. Aggregation of Aβ likely stimulates microglia early in disease and may instigate initial neuroinflammation (1). While gliosis has been shown to be beneficial in reducing plaque burden and mitigating amyloid-associated pathologies, long-term stimulation creates a permissive environment for chronic neuroinflammation. Pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6 further activate microglia and astrocytes, leading to both loss and gain of functions (2). These molecules have been shown to disrupt neuronal homeostasis and alter tau biology. Cytokine signaling has been linked to activation of kinases that phosphorylate tau, which may incite early tau dysfunction and ultimately influence misfolding and accumulation (3). Concurrently, there is deposition of complement proteins at neuronal synapses that can signal microglial pruning and initiate synapse loss (4). Microglia have also been implicated in facilitating the spread of tau via exosomes (5). Additionally, neuronal activity-dependent release of extracellular, misfolded tau may incite neuronal dysfunction or spread of tau pathology along synaptically connected neuronal populations. Ultimately, gliosis and chronic neuroinflammation combine with plaque and tangle pathologies to drive neurodegeneration in AD