IKK2/NF-κB Activation in Astrocytes Reduces Amyloid β Deposition: A Process Associated with Specific Microglia Polarization

Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number of amyloid plaques in the cerebral cortex and hippocampus. Interestingly, isolated primary astrocytes and microglia cells exhibit specific marker gene profiles which, in the case of microglia, point to an enhanced plaque clearance capacity. In contrast, direct IKK2/NF-κB activation in microglia results in a pro-inflammatory polarization program. Our findings suggest that IKK2/NF-κB signaling in astrocytes may activate paracrine mechanisms acting on microglia function but also on APP processing in neurons.

Differential polarization and the expression of efferocytosis receptor MerTK on M1 and M2 macrophages isolated from coronary artery disease patients

Background Differential polarization of macrophage into M1 and M2 mediates atherosclerotic plaque clearance through efferocytosis. Higher expression of Mer proto-oncogene tyrosine kinase (MerTK) on M2 macrophage helps in maintaining macrophage efferocytic efficiency. In healthy individuals, macrophage polarization into M1 and M2 occurs in tissues in concomitance with the acquisition of functional phenotypes depending on specific microenvironment stimuli. However, whether the macrophage differential polarization and MerTK expression vary in coronary artery disease (CAD) patients remain unknown. Objective This study aimed to elucidate the polarization of M1 and M2 macrophage from CAD patients as well as to investigate the expression of MerTK in these macrophage phenotypes. Methods A total of 14 (n) CAD patients were recruited and subsequently grouped into “no apparent CAD”, “non-obstructive CAD” and “obstructive CAD” according to the degree of stenosis. Thirty ml of venous blood was withdrawn to obtain monocyte from the patients. The M1 macrophage was generated by treating the monocyte with GMCSF, LPS and IFN-γ while MCSF, IL-4 and IL-13 were employed to differentiate monocyte into M2 macrophage. After 7 days of polarization, analysis of cell surface differentiation markers (CD86+/CD80+ for M1 and CD206+/CD200R+ for M2) and measurement of MerTK expression were performed using flow cytometry. Results Both M1 and M2 macrophage expressed similar level of CD86, CD80 and CD206 in all groups of CAD patients. MerTK expression in no apparent CAD patients was significantly higher in M2 macrophage compared to M1 macrophage [12.58 ± 4.40 vs. 6.58 ± 1.37, p = 0.040]. Conclusion Differential polarization of macrophage into M1 and M2 was highly dynamic and can be varied due to the microenvironment stimuli in atherosclerotic plaque. Besides, higher expression of MerTK in patients with the least coronary obstructive suggest its vital involvement in efferocytosis.

Quantitative 3D microscopy reveals a genetic network predicting the local activity of anti-Aβ compounds

Genetic and biochemical evidence suggests a role for amyloid-β (Aβ) in Alzheimer’s disease, yet many anti-Aβ treatments are clinically ineffective. Regional heterogeneity of efficacy may contribute to these disappointing results. Here we compared the regiospecificity of various anti-Aβ treatments by combining focused electrophoretic whole-brain clearing, amyloid labelling and light-sheet imaging with whole-brain analyses of plaque topology in Aβ-overexpressing mice. Aβ plaque numbers progressed from around 1’200’000 to 2’500’000 over a 9-month period. We then assessed the regiospecific plaque clearance in mice subjected to β-secretase inhibition, amyloid intercalation by polythiophenes, and anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance signatures, with polythiophenes emerging as potent anti-Aβ compounds with promising pharmacokinetic properties and the anti-Aβ antibody showing only minor effects. By aligning (25 µm)3 voxels that showed drug effectiveness to spatial transcriptomics atlases, we identified genes matching regiospecific Aβ clearance. As expected, Bace1 expression was highly correlated with the regiospecific efficacy of BACE inhibition. In addition, we found that voxels cleared by polythiophenes correlated with transcripts encoding synaptic proteins, whereas voxels cleared by BACE inhibition correlated with oligodendrocyte-specific genes. The differential regional susceptibility of distinct plaque populations to specific treatments may explain the clinical failure of anti-Aβ therapies, and suggests that combinatorial regimens may improve functional outcomes.

Capturing Amyloid-β Oligomers by Stirring with Microscaled Iron Oxide Stir Bars into Magnetic Plaques to Reduce Cytotoxicity toward Neuronal Cells

Soluble amyloid-β oligomers (oAβ42)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer’s disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring-induced capture of oAβ42 into magnetic plaques (mpAβ42) and activation of microglia on cellular plaque clearance was developed. With oAβ42 being effectively converted into mpAβ42, the neurotoxicity toward neuronal cells was thus greatly reduced. In addition to the good preservation of neurite outgrowth through the diminished uptake of oAβ42, neurons treated with oAβ42 under magnetic stirring also exhibited comparable neuron-specific protein expression to those in the absence of oAβ42. The phagocytic uptake of mpAβ42 by microglia was enhanced significantly as compared to the counterpart of oAβ42, and the M1 polarization of microglia often occurring after the uptake of oAβ42 restricted to an appreciable extent. As a result, the inflammation induced by pro-inflammatory cytokines was greatly alleviated.

Amyloid-β Immunotherapy on Alzheimer disease: Prevention and Therapeutic Target

Alzheimer disease (AD) is the most common neurodegenerative disease and form of dementia. The peptide amyloid-β (Aβ) is a most therapeutic target in AD on the basis of pathological and genetic suffices that supports a role for this molecule in the disease process. Studies show that Aβ immunotherapies (Active and passive) have been revealed to alleviate cerebral Aβ levels and improve cognition in animal models of AD. In humans, clinical trial phase 2 AN1792 conducted by Elan et al stated that Aβ vaccine was stopped when ~6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. In this study, Aβ immunotherapies will be discussed. Passive and active method of treatment in human and non-human primate with AD will also be review. Preclinical studies and the limited data from clinical trials and non-human primates’ evidence suggest Aβ immunotherapy as the most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. AD Biomarkers and imaging technology have improved greatly over the past 11 years and, in the future, can be used to identify pre-symptomatic, at-risk individuals who might benefit from Aβ immunotherapy

IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia

Background Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. Methods To determine whether microglia are involved in IL-1β-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar Aβ (fAβ) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1β or control were injected intraperitoneally with BrdU and hippocampal tissue was analyzed by flow cytometry. RNAseq analysis was conducted on microglia FACS sorted from the hippocampus of control or IL-1β-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04+ and MX04− microglia). Results Resident microglia (CD45loCD11b+) constituted > 70% of the MX04+ cells in both Phe- and IL-1β-treated conditions, and < 15% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of fAβ internalized by individual microglia. Instead, IL-1β increased the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. In addition, transcriptomic analyses revealed that IL-1β treatment was associated with large-scale changes in the expression of genes related to immune responses, proliferation, and cytokine signaling. Conclusions These studies show that IL-1β overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates Aβ plaque clearance.