Alzheimers disease (AD) is a neurodegenerative disease with major clinical hallmarks of memory loss, dementia, and cognitive impairment. Neuroinflammation is involved in the onset of several neurodegenerative disorders. Astrocyte is the most abundant type of glial cells in the central nervous system (CNS) and appears to be involved in the induction of neuroinflammation. Under stress and injury, astrocytes become astrogliotic leading to an upregulation of the expression of proinflammatory cytokines and chemokines, which are associated with the pathogenesis of AD. Cytokines and related molecules play roles in both neuroprotection and neurodegeneration in the CNS. During early AD pathogenesis, amyloid beta (Aβ), S100B and IL-1β could bring about a vicious cycle of Aβ generation between astrocytes and neurons leading to chronic, sustained and progressive neuroinflammation. In advanced stages of AD, TRAIL secreted from astrocytes have been shown to bind to death receptor 5 (DR5) on neurons to trigger apoptosis in a caspase-8-dependent manner. Furthermore, astrocytes could be reactivated by TGFβ1 to generate more Aβ and to undergo the aggravating astrogliosis. TGFβ2 was also observed to cooperate with Aβ to cause neuronal demise by destroying the stability of lysosomes in neurons. Inflammatory molecules can be either potential biomarkers for diagnosis or target molecules for therapeutic intervention. Understanding their roles and their relationship with activated astrocytes is particularly important for attenuating neuroinflammation in the early stage of AD. The main purpose of this review is to provide a comprehensive insight into the role of astrocytes in the neuroinflammatory pathogenesis of AD.

Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer’s disease (AD). However, how aging contributes to an increase in delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.