Diverse Inflammatory Responses in Transgenic Mouse Models of Alzheimer's Disease and the Effect of Immunotherapy on These Responses

Abstract

While the presence of an inflammatory response in AD (Alzheimer's disease) is well known, the data on inflammation are conflicting, suggesting that inflammation either attenuates pathology, exacerbates it or has no effect. Our goal was to more fully characterize the inflammatory response in APP (amyloid precursor protein) transgenic mice with and without disease progression. In addition, we have examined how anti-Aβ (amyloid β-peptide) immunotherapy alters this inflammatory response. We have used quantitative RT–PCR (reverse transcription–PCR) and protein analysis to measure inflammatory responses ranging from pro-inflammatory to anti-inflammatory and repair factors in transgenic mice that develop amyloid deposits only (APPSw) and amyloid deposits with progression to tau pathology and neuron loss [APPSw/NOS2−/− (nitric oxide synthase 2−/−)]. We also examined tissues from previously published immunotherapy studies. These studies were a passive immunization study in APPSw mice and an active vaccination study in APPSw/NOS2−/− mice. Both studies have already been shown to lower amyloid load and improve cognition. We have found that amyloid deposition is associated with high expression of alternative activation and acquired deactivation genes and low expression of pro-inflammatory genes, whereas disease progression is associated with a mixed phenotype including increased levels of some classical activation factors. Immunotherapy targeting amyloid deposition in both mouse models resulted in decreased alternative inflammatory markers and, in the case of passive immunization, a transient increase in pro-inflammatory markers. Our results suggest that an alternative immune response favours retention of amyloid deposits in the brain, and switching away from this state by immunotherapy permits removal of amyloid.

β-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice

“…HHcy results in an M1-type neuroinflammation in WT mice [5]. We have also previously shown that amyloid-depositing Tg2576 mice show an M2a phenotype when amyloid has accumulated [18]. In the present study, we show that HHcy resulted in increased expression of the M1 markers interleukin 1β (IL-1β), tumor necrosis factor α, IL-12 and IL-6 in the APP/PS1 mice (Figure 6).…”

Respiratory infection promotes T cell infiltration and amyloid-β deposition in APP/PS1 mice

“…However Stahl et al (2006) reported that intracerebral infection of Tg2576 mice with the neurotropic Borna disease virus resulted in a decrease in Abcontaining plaques in hippocampus (Stahl et al, 2006). Increases in microglial activation and in expression of inflammatory cytokines were observed, prompting the authors to suggest that an inflammatory environment might enhance clearance of Ab, which has been supported by some groups (Wilcock et al, 2011) but not by others (Koenigsknecht-Talboo and Landreth, 2005;Yamamoto et al, 2007). Indeed it has been shown that an inflammatory environment, such as predominates in AD, inhibits efficient phagocytosis (Koenigsknecht-Talboo and Landreth, 2005), whereas the interaction of microglia with T cells has also been shown to switch microglia from a phagocytic to an APC phenotype (Townsend et al, 2005).…”

Temporal profile of M1 and M2 responses in the hippocampus following early 24 h of neurotrauma

“…These changes include the expression of various cell surface molecules (e.g., receptors and adhesion molecules) [38,41,57] and the secretion of cytokines and free radicals that influence microglia activation in both the autocrine and paracrine manner [93]. In the M1 state microglial cells are phagocytic/cytotoxic in nature, release various proinflammatory factors (e.g., cytokines and free radicals) enhance neuronal loss [35], and drive or exacerbate neurological complications [2,24,62,90,91]. In contrast, M2 state microglia express anti-inflammatory factors that suppress inflammation and promote immune-regulatory and repair/remodeling processes [27,36,37,55,57,84].…”

“…Overall, the process of inflammation is demonstrated in two states of microglia/macrophage polarization (M1 and M2 responses) [43,55,57,91]. The expression of various cytokines, receptors, receptor ligands, enzymes, and matrix proteins [57,78,82,89] plays a pivotal role in the secondary injury as well as recovery/regenerative processes.…”