Aβ-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice

Abstract

A microglial response is part of the inflammatory processes in Alzheimer's disease (AD). We have used APP23 transgenic mice overexpressing human amyloid precursor protein with the Swedish mutation to characterize this microglia response to amyloid deposits in aged mice. Analyses with MAC-1 and F4/80 antibodies as well as in vivo labeling with bromodeoxyuridine demonstrate that microglia in the plaque vicinity are in an activated state and that proliferation contributes to their accumulation at the plaque periphery. The amyloid-induced microglia activation may be mediated by scavenger receptor A, which is generally elevated, whereas the increased immunostaining of the receptor for advanced glycation end products is more restricted. Although components of the phagocytic machinery such as macrosialin and Fc receptors are increased in activated microglia, efficient clearance of amyloid is missing seemingly because of the lack of amyloid-bound autoantibodies. Similarly, although up-regulation of major histocompatibility complex class II (IA) points toward an intact antigen-presenting function of microglia, lack of T and B lymphocytes does not indicate a cell-mediated immune response in the brains of APP23 mice. The similar characteristics of microglia in the APP23 mice and in AD render the mouse model suitable to study the role of inflammatory processes during AD pathogenesis.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Activation of PRRs leads to microglia reactivity, a process that could be both beneficial in removing toxic signals as well as deleterious in producing and enhancing toxicity. Brain and microglial up-regulation of PRRs members has been observed in human and experimental AD ( [3,67,21,258]). The Ab peptide was shown to activate microglia cells through the interaction with specific PRR: (a) scavenger receptors, including scavenger receptor class-A (SR-A), SR-B1 and CD36, that mediate Ab endocytosis and induce ROS production ( [46,66]); (b) macrophage receptor with collagenous domain (MARCO), a scavenger receptor that mediates adhesion of Ab to microglia and the cytoskeleton rearrangements induced by this peptide [84]; (c) the receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin superfamily, responsible for the induction of the inflammatory response stimulated by Ab ( [6,143,258]).…”

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

“…In the brains of human AD patients and transgenic AD mouse models, infiltration of activated astrocytes and microglia are seen in the area of A␤ plaques (Itagaki et al, 1989;Frautschy et al, 1998;Stalder et al, 1999;Bornemann et al, 2001;Matsuoka et al, 2001), which are characteristic components of an inflammatory process that develops around injury in the brain (McGeer and McGeer, 1999). Based on previous in vitro studies showing that RA inhibited the neurotoxic effect of activated microglia by suppressing the production of inflammatory cytokines and cytotoxic molecules (Dheen et al, 2005), we compared astrocytic and microglial reactivity in APP/PS1 mice treated with ATRA or vehicle as a control.…”

Erythropoietin and Oxidative Stress

“…Aβ also can release reactive oxygen species and lead to toxicity in neurons. In addition, Aβ can not only precipitate a significant inflammatory response with microglial activation and the secretion of TNF-α (Bornemann, et al, 2001), but also Aβ can elicit the neuronal expression of inducible nitric oxide synthase, peroxinitrite production, and neuronal apoptosis during an acute inflammatory response (Chong, et al, 2005e, Combs, et al., 2001. Furthermore, Aβ may lead to the induction of caspase mediated pathways (Nakagawa, et al, 2000, Troy, et al, 2001) that work in concert with oxidative stress (Tamagno, et al, 2003).…”