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Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease, which is currently diagnosed via clinical symptoms and nonspecific biomarkers (such as Aβ 1-42 , t-Tau, and p-Tau) measured in cerebrospinal fluid (CSF), which alone do not provide sufficient insights into disease progression. In this pilot study, these biomarkers were complemented with small-molecule analysis using non-target high-resolution mass spectrometry coupled with liquid chromatography (LC) on the CSF of three groups: AD, mild cognitive impairment (MCI) due to AD, and a non-demented (ND) control group. An open-source cheminformatics pipeline based on MS-DIAL and patRoon was enhanced using CSF- and AD-specific suspect lists to assist in data interpretation. Chemical Similarity Enrichment Analysis revealed a significant increase of hydroxybutyrates in AD, including 3-hydroxybutanoic acid, which was found at higher levels in AD compared to MCI and ND. Furthermore, a highly sensitive target LC-MS method was used to quantify 35 bile acids (BAs) in the CSF, revealing several statistically significant differences including higher dehydrolithocholic acid levels and decreased conjugated BA levels in AD. This work provides several promising small-molecule hypotheses that could be used to help track the progression of AD in CSF samples.

Historically neurodegenerative diseases, Alzheimer's disease (AD) in particular, have been viewed to be primarily caused and driven by neuronal mechanisms. Very recently, due to experimental, genetic, and epidemiologic evidence, immune mechanisms have entered the central stage and are now believed to contribute significantly to risk, onset, and disease progression of this class of disorders. Although immune activation of microglial cells may over time engage various signal transduction pathways, inflammasome activation, which represents a canonical and initiating pathway, seems to be one of the first responses to extracellular β-amyloid (Aβ) accumulation. Here we review the current understanding of inflammasome activation in AD.-Venegas, C., Heneka, M. T. Inflammasome-mediated innate immunity in Alzheimer's disease.

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APP Swe PSEN1 dE9 mice. By contrast, homogenates from brains of APP Swe PSEN1 dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APP Swe PSEN1 dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APP Swe PSEN1 dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.

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.

Pathogen-associated molecular patterns (PAMPs) and endogenous "danger" signals, known as danger-associated molecular patterns (DAMPs), released from cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved pattern recognition receptors (PRRs). Both PAMPs and DAMPs directly induce proinflammatory cascades and trigger the formation of the inflammasome, mediating the release of cytokines. Here, we highlight the role of DAMPs, including amyloid β (Aβ), high-mobility group box 1 (HMGB1), the S100 family proteins, chromogranin A, and nucleic acids, in the innate-immune activation during the course of Alzheimer disease (AD), the most frequent neurodegenerative disorder., (© Society for Leukocyte Biology.)

Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease with no specific treatment at present. Several healthy lifestyle options and over-the-counter drugs that it has been suggested delay the onset of the disease are in an experimental phase, but it is unclear whether they will have any therapeutic value against AD. We assayed physical exercise and melatonin in 3xTg-AD male mice aged from 6 to 12 months, therefore from moderate to advanced phases of AD pathology. Analysis of behavior and brain tissue at termination showed differential patterns of neuroprotection for the 2 treatments. Both treatments decreased soluble amyloid β oligomers, whereas only melatonin decreased hyperphosphorylated tau. Melatonin was effective against the immunosenescence that 3xTg-AD mice present. Voluntary physical exercise protected against behavioral and psychological symptoms of dementia such as anxiety, a lack of exploration, and emotionality. Both treatments protected against cognitive impairment, brain oxidative stress, and a decrease in mitochondrial DNA (mtDNA). Interestingly, only the combined treatment of physical exercise plus melatonin was effective against the decrease of mitochondrial complexes. Therefore, melatonin plus physical exercise may exert complementary, additive, or even synergistic effects against a range of disturbances present in AD., (Copyright © 2012 Elsevier Inc. All rights reserved.)