Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid‐beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2‐photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post‐challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid‐beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.

Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.

Background Alzheimer's disease (AD) is the most frequent degenerative dementia, with a prevalence expected to increase in coming years. Deposits of amyloid and hyperphosphorylated TAU protein constitute the characteristic pathological findings of the disease, although its etiology in sporadic cases is still unknown. Cholesterol metabolism has been related to AD through multiple evidences. Filipin is a macrolide that binds to cholesterol and allows its quantification. We consider assessing whether there are differences in cholesterol content determined by Filipin’s fluorescence (FF) in peripheral blood mononuclear cells (PBMCs) of patients with AD and healthy controls. Method Cross‐sectional study.Patients diagnosed with AD at different stages with support of biomarkers in cerebrospinal fluid (CSF) and cognitively healthy controls were included. PBMCs obtained from whole blood were co stained with Filipin and antibodies specific for several leucocyte subpopulations (CD8, CD4, CD11b, CD19, CD14 and CD16).FF was measured by flow cytometry in PBMCs and in different subpopulations. Results N=61 (51 AD,10 controls);When the whole PBMCs were compared, no significant differences in filipin fluorescence among diagnostic groups were observed (AD 1280, controls 1218.9; p=0.65). However, subpopulation analysis revealed significant decrease in cholesterol content in CD14+ cells of patients with AD (AD 2623.9, controls 4433.2; p = 0.007). Differences in cholesterol content in this CD14+ subpopulation were also significant in ApoE4 carriers (2427.1 in carriers, 3130.43 non‐carriers, p=0.017) Conclusions Cholesterol content of CD14+ peripheral blood mononuclear cells could be a neurodegeneration biomarker and it could be related with AD,which supports the involvement of cellular cholesterol homeostasis in the pathophysiology of the disease.