Amyloid Deposition and Inflammation in APPswe/PS1dE9 Mouse Model of Alzheimers Disease

Abstract

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles associated with chronic inflammation. APPswe/PS1dE9 is an AD mouse model bearing mutant transgenes of amyloid precursor protein and presenilin-1. Amyloid deposition is present in this mouse model at early stage of life. However, the progression of inflammation and its relationship with amyloid deposition have not been characterized. Here we showed that amyloid plaques were present at 4 months of age and increased with age. CD11b-positive microglia clusters appeared in hippocampus and neocortex at 4 months of age and increased with age. Clustered glial fibrillary acidic protein (GFAP)-positive astrocytes were observed in hippocampus and cortex after 6 months of age and increased with age. Double staining with CD11b/GFAP antibody and thioflavin S showed clustered microglia and astrocytes were in close association with amyloid plaques. Expression of TNF-alpha was detected at 8 months of age, while IL-1 beta, IL-6 and MCP-1 at 10 months. These cytokines increased with age. Double immunostaining of cell specific marker and cytokine indicated TNF-alpha, IL-1 beta, IL-6 and MCP-1 were expressed by activated microglia and a small part of activated astrocytes. MCP-1 was also expressed by neurons, which support recent finding that MCP-1 expression was increased in neurons of AD patient. These results demonstrate amyloid plaques and its associated inflammatory response developed at early stage of life and progressively increased with age, both activated glia and neurons are involved in chronic inflammation in AD. APPswe/PS1dE9 model provides a mean for studying the mechanisms and novel therapeutics for AD.

Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice

“…The monitoring of inflammation in APPswePS1dE9 versus WT mice at 3, 6 and 12 months of age showed that APPswePS1dE9 mice displayed cytokine production, in particular IL-1β in cortex at 12 months of age and hippocampus from 6 months, but TNF-α levels increased only in hippocampus at 12 months and were less than 10 pg/mg protein as previously described [37,38]. In line with our work, Jin et al .…”

“…Recently, we showed, in primary cultures of neurons, astrocytes and microglia, that IL-1β induced autophagy with accumulation of many acidic vesicles loaded with autophagic markers (p62 and LC3) in microglia, whereas Aβ42 prevented the effects of exogenous IL-1β in the production of inflammatory factors and in autophagy impairment [53]. In this present study, we wanted to explore correlations between autophagy and inflammation in vivo by using APPswePS1dE9 mice which displayed amyloid plaques and an inflammatory response at an early stage of the life and progressively increase with age [37,38]. However, their longitudinal status of autophagy has never been studied.…”

“…Occasional deposits can be found in mice as young as six months of age and plaques are abundant in hippocampus and cortex by nine months of age. Furthermore, in this APPswePS1dE9 mouse model of AD, amyloid plaques and its associated inflammatory response develop at early stage of the life and progressively increase with age [36,37]. …”

Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition

“…It has been established that CD11b microglia cell clusters were observed as early as 4 months of age [87]. Other studies established that particularly the microglia cells proliferate around A β plaques, without astrocyte proliferation in these animals; indeed, age-related increases in proliferation in this mouse model were due to increases in newborn BrdU+ cells coexpressing markers for activated microglia [30].…”

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

“…Therefore, we Although Ruan et al (2009) Follow-up measurements in our study were performed 5 and 10 weeks after the baseline study and were combined with the idea that microglial activation could be modulated by a PPAR-γ agonist. PPAR-γ is a nuclear receptor that plays an important role in inflammatory processes.…”