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Extracorporeal apheresis therapy for Alzheimer disease-targeting lipids, stress, and inflammation.
Bornstein, SR, Voit-Bak, K, Rosenthal, P, Tselmin, S, Julius, U, Schatz, U, Boehm, BO, Thuret, S, Kempermann, G, Reichmann, H, et al
Molecular psychiatry. 2020;(2):275-282
Abstract
Current therapeutic approaches to Alzheimer disease (AD) remain disappointing and, hence, there is an urgent need for effective treatments. Here, we provide a perspective review on the emerging role of "metabolic inflammation" and stress as a key factor in the pathogenesis of AD and propose a novel rationale for correction of metabolic inflammation, increase resilience and potentially slow-down or halt the progression of the neurodegenerative process. Based on recent evidence and observations of an early pilot trial, we posit a potential use of extracorporeal apheresis in the prevention and treatment of AD. Apolipoprotein E, lipoprotein(a), oxidized LDL (low density lipoprotein)'s and large LDL particles, as well as other proinflammatory lipids and stress hormones such as cortisol, have been recognized as key factors in amyloid plaque formation and aggravation of AD. Extracorporeal lipoprotein apheresis systems employ well-established, powerful methods to provide an acute, reliable 60-80% reduction in the circulating concentration of these lipid classes and reduce acute cortisol levels. Following a double-membrane extracorporeal apheresis in patients with AD, there was a significant reduction of proinflammatory lipids, circulating cytokines, immune complexes, proinflammatory metals and toxic chaperones in patients with AD. On the basis of the above, we suggest designing clinical trials to assess the promising potential of such "cerebropheresis" treatment in patients with AD and, possibly, other neurodegenerative diseases.
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Microglial Store-operated Calcium Signaling in Health and in Alzheimer's Disease.
McLarnon, JG
Current Alzheimer research. 2020;(12):1057-1064
Abstract
The dysregulation of calcium signaling mechanisms in neurons has been considered a contributing factor to the pathogenesis evident in early-onset Alzheimer's Disease (AD). However, considerably less is known concerning the possible impairment of Ca2+ mobilization in resident immune cell microglia. This review considers findings which suggest that a prominent pathway for non-excitable microglial cells, store-operated calcium entry (SOCE), is altered in the sporadic form of AD. The patterns of Ca2+ mobilization are first discussed with platelet-activating factor (PAF) stimulation of SOCE in adult, fetal and immortalized cell-line, human microglia in the healthy brain. In all cases, PAF was found to induce a rapid transient depletion of Ca2+ from endoplasmic reticulum (ER) stores, followed by a sustained entry of Ca2+ (SOCE). A considerably attenuated duration of SOCE is observed with ATP stimulation of human microglia, suggested as due to agonist actions on differential subtype purinergic receptors. Microglia obtained from AD brain tissue, or microglia treated with full-length amyloid-β peptide (Aβ42), show significant reductions in the amplitude of SOCE relative to controls. In addition, AD brain and Aβ42-treated microglia exhibit decreased levels of Ca2+ release from ER stores compared to controls. Changes in properties of SOCE in microglia could lead to altered immune cell response and neurovascular unit dysfunction in the inflamed AD brain.
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From Polygenic Scores to Precision Medicine in Alzheimer's Disease: A Systematic Review.
Harrison, JR, Mistry, S, Muskett, N, Escott-Price, V
Journal of Alzheimer's disease : JAD. 2020;(4):1271-1283
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Abstract
BACKGROUND Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual's risk alleles, have been used to draw inferences about the pathological processes underpinning AD. OBJECTIVE This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. METHODS We searched the literature from July 2008-July 2018 following PRISMA guidelines. RESULTS 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. CONCLUSION PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.
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Evaluation of CD33 as a genetic risk factor for Alzheimer's disease.
Estus, S, Shaw, BC, Devanney, N, Katsumata, Y, Press, EE, Fardo, DW
Acta neuropathologica. 2019;(2):187-199
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Abstract
In 2011, genome-wide association studies implicated a polymorphism near CD33 as a genetic risk factor for Alzheimer's disease. This finding sparked interest in this member of the sialic acid-binding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found that CD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying the CD33 genetic association with Alzheimer's disease. The allele that protects from Alzheimer's disease acts predominately to increase a CD33 isoform lacking exon 2 at the expense of the prototypic, full-length CD33 that contains exon 2. Since this exon encodes the sialic acid ligand-binding domain, the finding that the loss of exon 2 was associated with decreased Alzheimer's disease risk was interpreted as meaning that a decrease in functional CD33 and its associated immune suppression was protective from Alzheimer's disease. However, this interpretation may need to be reconsidered given current findings that a genetic deletion which abrogates CD33 is not associated with Alzheimer's disease risk. Therefore, integrating currently available findings leads us to propose a model wherein the CD33 isoform lacking the ligand-binding domain represents a gain of function variant that reduces Alzheimer's disease risk.
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Pathological Changes in Alzheimer's Disease Analyzed Using Induced Pluripotent Stem Cell-Derived Human Microglia-Like Cells.
Xu, M, Zhang, L, Liu, G, Jiang, N, Zhou, W, Zhang, Y
Journal of Alzheimer's disease : JAD. 2019;(1):357-368
Abstract
Microglia constitute the majority of innate immune cells in the brain, and their dysfunction is associated with various central nervous system diseases. Human microglia are extremely difficult to obtain experimentally, thereby limiting studies on their role in complex diseases. Microglia derived from human stem cells provide new tools to assess the pathogenesis of complex diseases and to develop effective treatment methods. This study aimed to develop a reliable method to derive human microglial-like cells (iMGLs) from induced pluripotent stem cells (iPSCs) expressing microglia-specific markers IBA1 and TMEM119 and respond to lipopolysaccharide (LPS) stimulation. Thereafter, we compared iMGL functions from Alzheimer's disease (AD) patients and cognitive normal controls (CNCs). AD-iMGLs displayed stronger phagocytic ability with or without stimulation. High LPS concentrations (>2μg/ml) caused death in CNC-iMGLs, while AD-iMGLs did not display significant cell death. Cytokine analysis revealed that TNF-α, IL-6, and IL-10 secreted by AD-iMGLs were significantly increased upon LPS stimulation compared to those in CNC-iMGLs. The present results indicate that AD-iMGLs exhibit significant inflammatory characteristics and can reflect some pathological changes in microglia in AD, thereby providing new valuable tools to screen candidate drugs for AD and to elucidate the mechanisms underlying AD pathogenesis.
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The genetic landscape of Alzheimer disease.
Carmona, S, Hardy, J, Guerreiro, R
Handbook of clinical neurology. 2018;:395-408
Abstract
Alzheimer disease (AD), a progressive and neurodegenerative disease, is the most common form of dementia with high incidence in elderly people. Neuropathologically the disease is defined by the combined presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of phosphorylated tau protein. Genetically, the first clues were provided by genetic linkage studies that led to the identification of APP, PSEN1, and PSEN2 mutations as the main causes of autosomal-dominant early-onset AD. Another important hallmark was the identification of the APOE ɛ4 allele as a risk factor for late-onset AD. Over the last 20 years the development and implementation of new genetic and genomic technologies have allowed the identification of other genetic players in this disease. Genome-wide association studies identified more than 20 loci with common variability having small contributions to the susceptibility of AD. The majority of the genes mapped in these loci are known to be involved in specific biologic pathways: cholesterol metabolism, immune response, and endocytosis. More recently, the application of next-generation sequencing (mainly whole-exome sequencing) has begun to reveal the contribution of rarer variants with medium effects on risk for AD. This area of research has come a long way with many and important results allowing a better understanding of the disease. More efforts are still needed, however, to fully understand the etiology of this disease in order to establish reliable individual predictive models and put us closer to the development of a curative, preventive, or modulator drug.
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Neuroinflammation, immune system and Alzheimer disease: searching for the missing link.
Guerriero, F, Sgarlata, C, Francis, M, Maurizi, N, Faragli, A, Perna, S, Rondanelli, M, Rollone, M, Ricevuti, G
Aging clinical and experimental research. 2017;(5):821-831
Abstract
Due to an increasingly aging population, Alzheimer disease (AD) represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. Several hypotheses on AD pathogenesis have been proposed and current therapeutical strategies have shown limited effectiveness. In the last decade, more evidence has supported a role for neuroinflammation and immune system dysregulation in AD. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Amyloid-β peptides that aggregate extracellularly in the typical neuritic plaques generate a constant inflammatory environment. This causes a prolonged activation of microglial and astroglial cells that potentiate neuronal damage and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuroinflammation, the immune system and AD. Hence, a thorough investigation of the neuroinflammatory and immune system pathways that impact neurodegeneration and novel exciting findings such as microglia-derived microvesicles, inflammasomes and signalosomes will ultimately enhance our understanding of the pathological process. Eventually, we should proceed with caution in defining a causal or consequential role of neuroinflammation in AD, but rather focus on identifying its exact pathological contribution.
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TLR4 is a link between diabetes and Alzheimer's disease.
Huang, NQ, Jin, H, Zhou, SY, Shi, JS, Jin, F
Behavioural brain research. 2017;:234-244
Abstract
Recently, more and more studies have shown that there is an essential link between diabetes mellitus (DM) and Alzheimer's disease (AD). In addition, innate immunity plays an important role in the occurrence and development of DM and AD, which increase the risk of developing type 2 diabetes (T2D) and AD. Although the pathogenesis of those diseases is still a matter of debate, the important role of Toll-like receptor 4 (TLR4) in the two diseases has been receiving much attention at present. TLR4 and insulin resistance do have close ties, and chronic TLR4 activation may contribute to the insulin resistance. Aside from this, TLR4-mediated chronic inflammation also causes many DM complications such as diabetic nephropathy, diabetic retinopathy and diabetic neuropathy and has a profound impact on the internal environment of the body and brain's microenvironment. In parallel, TLR4 is widely distributed in the brain and also has an important role in the central nervous system (CNS) via regulation of neuroinflammation. The cerebrum under the circumstances of insulin resistance may lead to mitochondrial dysfunction in neurons. Interestingly, in the initial stage, the activation of TLR4 has a useful scavenging effect on amyloid beta (Aβ), but chronic long-term activation leads to Aβ deposition in the brain. Therefore we speculate that the TLR4 signaling pathway may be a potential link between DM and AD.