Astrocytes: Implications for Neuroinflammatory Pathogenesis of Alzheimers Disease

Abstract

Alzheimer's 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.

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

“…Although most research has focused on the effect of Tau protein tangles and A␤ plaques on neuronal function and survival, it is now well established that astrocytes also play a role in AD pathology (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In the CNS, astrocytes are indispensable for the support of neurons.…”

“…In the CNS, astrocytes are indispensable for the support of neurons. However, astrocytes can also adopt an activated state where they start to migrate and proliferate and induce inflammatory and proapoptotic cell signaling pathways (8,10,15,16). Astrocytic reactivation has been observed in many neurodegenerative diseases, including AD, and is thought to occur as a response to oxidative stress and cytokine release (8, 10 -12, 16 -18).…”

ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice

“…In neurodegeneration models, early stages are often associated with atrophy of astroglia, whereas later, astrocytosis and astrocyte activation contribute to the neuroinflammatory component of neurodegeneration. 42,43 Noteworthy, it was shown that proNGF produced by reactive astrocytes in response to oxidative stress promotes motoneuron death in a p75…”

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

“…Although APP and S100B have previously been implicated in oxidative stress and cell death, constitutive over-expression of these and other HSA21 genes would also predict upregulation of inflammatory responses (astrocytosis), leading to a skewed gliocentric progenitor phenotype. The ongoing cell death and inflammation from APP and S100B promote reactive astrocytosis and astrocytes secrete S100B, causing further cell injury and death (Li et al, 2011). This same mechanism of injury in the mature brain could also take place within the progenitor population during development.…”