Dataset Information

Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease.

ABSTRACT:

Background

Sepsis, a leading cause for intensive care unit admissions, causes both an acute encephalopathy and chronic brain dysfunction in survivors. A history of sepsis is also a risk factor for future development of dementia symptoms. Similar neuropathologic changes are associated with the cognitive decline of sepsis and Alzheimer's disease (AD), including neuroinflammation, neuronal death, and synaptic loss. Amyloid plaque pathology is the earliest pathological hallmark of AD, appearing 10 to 20 years prior to cognitive decline, and is present in 30% of people over 65. As sepsis is also more common in older adults, we hypothesized that sepsis might exacerbate amyloid plaque deposition and plaque-related injury, promoting the progression of AD-related pathology.

Methods

We evaluated whether the brain's response to sepsis modulates AD-related neurodegenerative changes by driving amyloid deposition and neuroinflammation in mice. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in APP/PS1-21 mice, a model of AD-related β-amyloidosis. We performed CLP or sham surgery at plaque onset (2 months of age) and examined pathology 2 months after CLP in surviving mice.

Results

Sepsis significantly increased fibrillar amyloid plaque formation in the hippocampus of APP/PS1-21 mice. Sepsis enhanced plaque-related astrocyte activation and complement C4b gene expression in the brain, both of which may play a role in modulating amyloid formation. CLP also caused large scale changes in the gut microbiome of APP/PS1 mice, which have been associated with a pro-amyloidogenic and neuroinflammatory state.

Conclusions

Our results suggest that experimental sepsis can exacerbate amyloid plaque deposition and plaque-related inflammation, providing a potential mechanism for increased dementia in older sepsis survivors.

SUBMITTER: Basak JM

PROVIDER: S-EPMC8057119 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:PurposeAmyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer's disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies.MethodsIn this study 238 [(11)C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [(11)C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69?±?8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5?±?8 years) and 51 healthy controls (mean age 67.4?±?6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28?±?15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype.Results[(11)C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [(11)C]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [(11)C]PIB retention was observed in MCI ApoE ?4 carriers compared to non-ApoE ?4 carriers (p?<?0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted.ConclusionThis study demonstrated the robustness of [(11)C]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.

Project description:BackgroundReactive microglia are associated with ?-amyloid (A?) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear A? deposits although they mainly exist in an "activated" state. Oligomeric A? (oA?), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar A? (fA?). However, the role of the different A? forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.ResultsWe demonstrated that A?(1-42) fibrils, not A?(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oA?(1-42) not only attenuated fA?(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fA?(1-42). Compared with the fA?(1-42) treatment, the oA?(1-42) treatment resulted in a rapid and transient increase in interleukin 1? (IL-1?) level and produced higher levels of tumor necrosis factor-? (TNF-?), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fA?(1-42)-induced microglia was decreased by IL-1?, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-?B (NF-?B) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oA?-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oA?(1-42) stimulation reduced the mRNA expression of CD36, integrin ?1 (Itgb1), and Ig receptor Fc?RIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oA?(1-42) or the inflammatory and oxidative milieu (IL-1?, LPS or t-BHP) significantly downregulated the fA?(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells.ConclusionThese results imply that A? oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of A? fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.