Abstract
Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer’s disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1ΔE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.
Highlights
Neuroinflammation is a hallmark of Alzheimer’s disease (AD) pathology, and is considered a major contributor to AD pathogenesis (Zhang et al, 2013; Heneka et al, 2015)
We have previously shown that microglia produce tumor necrosis factor (TNF) and interleukin 1β (IL1β) in 9-month-old Tg mice (Babcock et al, 2015) and LPS is known as a strong inducer of microglial cytokine production (Perry et al, 2007)
The TNF mRNA levels in neocortex were significantly influenced by the LPS administration [F(1,36) = 38.6, p < 0.0001, two-way ANOVA], giving rise to a twofold to fourfold increase in wild type (Wt) [p < 0.0001, Tukey’s] and Tg [p < 0.05] mice (Figure 1A)
Summary
Neuroinflammation is a hallmark of Alzheimer’s disease (AD) pathology, and is considered a major contributor to AD pathogenesis (Zhang et al, 2013; Heneka et al, 2015). Activated microglia produce inflammatory molecules, such as tumor necrosis factor (TNF), and interleukin 1β (IL1β) (Eggen et al, 2013), molecules which have been shown to be increased in AD brains along with multiple other inflammatory molecules (Griffin et al, 1989; Bauer et al, 1991; Tarkowski et al, 2003). Markers of inflammation, such as C-reactive protein and TREM2, are elevated in blood and/or cerebrospinal fluid years before the onset of dementia (Schmidt et al, 2002; Suárez-Calvet et al, 2016; Lai et al, 2017). Epidemiological studies have shown an effect of non-steroidal anti-inflammatory drugs in the risk of developing AD, beneficial effects have not been replicated in randomized clinical trials (Deardorff and Grossberg, 2017)
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