Linking lipids to Alzheimer's disease: cholesterol and beyond

Nature reviews. Neuroscience, Journal Year: 2011, Volume and Issue: 12(5), P. 284 - 296

Published: March 30, 2011

Language: Английский

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Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2012, Volume and Issue: 2(3), P. a006312 - a006312

Published: Jan. 10, 2012

Apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer disease (AD); ε4 allele increases and ε2 protective. In central nervous system (CNS), apoE produced by glial cells, present in high-density-like lipoproteins, interacts with several receptors that are members of low-density lipoprotein receptor (LDLR) family, a protein binds to amyloid-β (Aβ) peptide. There variety mechanisms which isoform may influence AD. substantial evidence differential effects on AD influenced ability affect Aβ aggregation clearance brain. Other also likely play role CNS function as well AD, including synaptic plasticity, cell signaling, lipid transport metabolism, neuroinflammation. ApoE receptors, LDLRs, Apoer2, very (VLDLRs), receptor-related 1 (LRP1) appear both metabolism toxicity. Therapeutic strategies based include influencing apoE/Aβ interactions, structure, lipidation, LDLR family member function, signaling. Understanding normal disease-related biology connecting apoE, provide novel insights into pathogenesis treatment.

Language: Английский

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Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders

Journal of Molecular Medicine, Journal Year: 2016, Volume and Issue: 94(7), P. 739 - 746

Published: June 9, 2016

Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with role in cholesterol metabolism cardiovascular disease. It has since emerged risk factor (causative gene) Alzheimer's disease other neurodegenerative disorders. Detailed understanding of the structural features three isoforms (apoE2, apoE3, apoE4), which differ by only single amino acid interchange, elucidated their unique functions. ApoE2 apoE4 increase heart disease: apoE2 increases atherogenic levels (it binds poorly to LDL receptors), preferentially triglyceride-rich, very lipoproteins, leading downregulation receptors). ApoE4 also diseases, decreases age onset, or alters progression. likely causes neurodegeneration secondary its abnormal structure, caused an interaction between carboxyl- amino-terminal domains, called domain interaction. When neurons are stressed injured, they synthesize apoE redistribute neuronal repair remodeling. However, because altered undergoes neuron-specific proteolysis, generating neurotoxic fragments (12–29 kDa) that escape secretory pathway cause mitochondrial dysfunction cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented small-molecule structure correctors block converting molecule resembles apoE3 both structurally functionally. Structure potential therapeutic approach reduce neurological

Language: Английский

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Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases

Neurobiology of Disease, Journal Year: 2014, Volume and Issue: 72, P. 3 - 12

Published: Aug. 27, 2014

Language: Английский

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Emerging roles of Wnts in the adult nervous system

Nature reviews. Neuroscience, Journal Year: 2009, Volume and Issue: 11(2), P. 77 - 86

Published: Dec. 16, 2009

Language: Английский

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Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

PLoS ONE, Journal Year: 2010, Volume and Issue: 5(11), P. e13950 - e13950

Published: Nov. 15, 2010

Background Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified first strongly supported LOAD susceptibility genes since discovery involvement APOE in early 1990s. We have now exploited these GWAS datasets to uncover key pathophysiological processes. Methodology applied a recently developed tool for mining data biologically meaningful information dataset. The principal findings were then tested an independent Principal Findings found significant overrepresentation signals pathways related cholesterol metabolism and immune response both two largest LOAD. Significance Processes innate previously been implicated by pathological epidemiological disease, but it has unclear whether those reflected primary aetiological events or consequences process. Our evidence from demonstrates that processes are aetiologically relevant, suggests they may be suitable targets novel existing therapeutic approaches.

Language: Английский

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History and progress of hypotheses and clinical trials for Alzheimer’s disease

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Aug. 23, 2019

Abstract Alzheimer’s disease (AD) is a neurodegenerative characterized by progressive memory loss along with neuropsychiatric symptoms and decline in activities of daily life. Its main pathological features are cerebral atrophy, amyloid plaques, neurofibrillary tangles the brains patients. There various descriptive hypotheses regarding causes AD, including cholinergic hypothesis, tau propagation mitochondrial cascade calcium homeostasis neurovascular inflammatory metal ion lymphatic system hypothesis. However, ultimate etiology AD remains obscure. In this review, we discuss related clinical trials. Wealthy puzzles lessons have made it possible to develop explanatory theories identify potential strategies for therapeutic interventions AD. The combination hypometabolism autophagy deficiency likely be causative factor We further propose that fluoxetine, selective serotonin reuptake inhibitor, has treat

Language: Английский

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Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2011, Volume and Issue: 83(2), P. 124 - 137

Published: Nov. 5, 2011

Abstract

Cell plasticity operates alongside other sources of cell-to-cell heterogeneity, such as genetic mutations and variation in signaling, together preventing most cancer therapies from being curative. The predominant methods quantifying tumor-drug response operate on snapshot, population-level measurements therefore lack evolutionary dynamics, which are particularly critical for dynamic processes plasticity. Here we apply a lineage tree-based adaptation hidden Markov model that employs single cell lineages input to learn the characteristic patterns phenotypic heterogeneity state transitions an unsupervised fashion. To benchmark our model, paired fate with either lifetimes or individual cycle phase lengths synthetic data demonstrated successfully classifies cells within experimentally tractable dataset sizes. As application, analyzed experimental same non-cancer populations under various treatments. We find each case multiple phenotypically distinct states exist, significant unique drug responses. In total, this framework allows flexible classification across lineages.

Language: Английский

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Resting-state functional connectivity in normal brain aging

Neuroscience & Biobehavioral Reviews, Journal Year: 2013, Volume and Issue: 37(3), P. 384 - 400

Published: Jan. 17, 2013

Language: Английский

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Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

Journal of Biological Chemistry, Journal Year: 2011, Volume and Issue: 287(4), P. 2678 - 2688

Published: Dec. 3, 2011

Language: Английский

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