Human amyloid β‐induced neuroinflammation is an early event in neurodegeneration

Abstract

Using a human amyloid beta (Abeta) intracerebroventricular infusion mouse model of Alzheimer's disease-related injury, we previously demonstrated that systemic administration of a glial activation inhibitor could suppress neuroinflammation, prevent synaptic damage, and attenuate hippocampal-dependent behavioral deficits. We report that Abeta-induced neuroinflammation is an early event associated with onset and progression of pathophysiology, can be suppressed by the glial inhibitor over a range of intervention start times, and is amenable to suppression without inhibiting peripheral tissue inflammatory responses. Specifically, hippocampal neuroinflammation and neurodegeneration occur in close time proximity at 4-6 weeks after the start of infusion. Intraperitoneal administration of inhibitor for 2-week intervals starting at various times after initiation of Abeta infusion suppresses progression of pathophysiology. The glial inhibitor is a selective suppressor of neuroinflammation, in that it does not block peripheral tissue production of proinflammatory cytokines or markers of B- and T-cell activation after a systemic lipopolysaccharide challenge. These results support a causal link between neuroinflammation and neurodegeneration, have important implications for future therapeutic development, and provide insight into the relative time window for targeting neuroinflammation with positive neurological outcomes.

Inflammatory Response in the Hippocampus of PS1M146L/APP751SLMouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic

“…Neuroinflammation is a key feature of AD pathology (Meda et al, 2001;Dudal et al, 2004;Craft et al, 2006). However, its role is still conflictive.…”

“…Secondary to A␤ accumulation, there is an inflammatory response characterized by activated microglia and reactive astrocytes. Activated inflammatory cells could mediate neuronal damage by producing toxic products, such as inflammatory cytokines, excitatory amino acids, reactive oxygen intermediates and other factors (Mrak and Griffin, 2005;Craft et al, 2006;Ralay Ranaivo et al, 2006;Zipp and Aktas, 2006). This potential cytotoxic effect was further emphasized by clinical studies demonstrating that the symptoms of AD could be attenuated by nonsteroidal antiinflammatory drugs (Aisen, 2000;McGeer and McGeer, 2007).…”

Phospholipases A2Mediate Amyloid-β Peptide-Induced Mitochondrial Dysfunction

“…Our previous study identified the role of iPLA 2 and cPLA 2 in oxidant damage of astrocytes, and the effects of oxidants on cPLA 2 are mediated through activation of the MAPK pathways (Xu et al, 2003). A␤ has been shown to stimulate glial cells and cause neuronal death (Butterfield, 2002;Dahlgren et al, 2002;Craft et al, 2006). Abramov et al (2004) attributed the ability of A␤ to cause ROS production in astrocytes through activation of NADPH oxidase, and, in turn, this leads to depolarization of mitochondria .…”

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…The inflammation can be acute or chronic. The inflammatory reaction that involves in most neurodegenerative diseases (Craft et al 2006;Liu et al 2013;Pizza et al 2011;Sudduth et al 2013;Varnum and Ikezu 2012), is often termed ''neuroinflammation''. Microglia, which is supposed to be the resident macrophages of the brain, and atrocities are the main cells that involve in this process.…”