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Folia Neuropathologica 2019Early reviews identified over 20 risk factors associated with Alzheimer's disease (AD) including age, familial inheritance, exposure to aluminium, traumatic brain injury... (Review)
Review
Early reviews identified over 20 risk factors associated with Alzheimer's disease (AD) including age, familial inheritance, exposure to aluminium, traumatic brain injury (TBI), and associated co-morbidities such as vascular disease and infection. In the light of recent evidence, this review reconsiders these risk factors, identifies those currently regarded as important, and discusses various hypotheses to explain how they may cause AD. Rare forms of early-onset familial AD (EO-FAD) are strongly linked to causal gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (LO-SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) and many other genes, vascular disease, TBI and risk factors associated with diet, the immune system, mitochondrial function, metal exposure, and infection are all implicated. These risk factors may act collectively to cause AD pathology: 1) by promoting the liberation of oxygen free radicals with age, 2) via environmental stress acting on regulatory genes early and later in life ('dual hit' hypothesis), or 3) by increasing the cumulative 'allostatic load' on the body over a lifetime. As a consequence, life-style changes which reduce the impact of these factors may be necessary to lower the risk of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Apolipoproteins E; Humans; Mutation; Risk Factors
PubMed: 31556570
DOI: 10.5114/fn.2019.85929 -
Annual Review of Pathology Jan 2022Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult... (Review)
Review
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult to develop therapeutics for AD due to its complex nature. Nevertheless, recent advancements in imaging technology and the development of innovative experimental techniques have allowed researchers to perform in-depth analyses to uncover the pathogenic mechanisms of AD. An important consideration when studying late-onset AD is its major genetic risk factor, apolipoprotein E4 (apoE4). Although the exact mechanisms underlying apoE4 effects on AD initiation and progression are not fully understood, recent studies have revealed critical insights into the apoE4-induced deficits that occur in AD. In this review, we highlight notable studies that detail apoE4 effects on prominent AD pathologies, including amyloid-β, tau pathology, neuroinflammation, and neural network dysfunction. We also discuss evidence that defines the physiological functions of apoE and outlines how these functions are disrupted in apoE4-related AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Apolipoproteins E; Humans
PubMed: 34460318
DOI: 10.1146/annurev-pathmechdis-030421-112756 -
Molecular Neurodegeneration Nov 2022Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.
Topics: Humans; Alzheimer Disease; Apolipoproteins E; Apolipoprotein E4; Amyloid beta-Peptides; Plaque, Amyloid; Alleles
PubMed: 36348357
DOI: 10.1186/s13024-022-00574-4 -
Biological Psychiatry Feb 2018Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface... (Review)
Review
Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not limited to the metabolism, aggregation, and toxicity of amyloid-β peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation. Emerging knowledge on apoE-related pathways in the pathophysiology of AD presents new opportunities for AD therapy. We describe the biochemical and biological features of apoE and apoE receptors in the central nervous system. We also discuss the evidence and mechanisms addressing differential effects of apoE isoforms and the role of apoE receptors in AD pathogenesis, with a particular emphasis on the clinical and preclinical studies related to amyloid-β pathology. Finally, we summarize the current strategies of AD therapy targeting apoE, and postulate that effective strategies require an apoE isoform-specific approach.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Humans; Low Density Lipoprotein Receptor-Related Protein-1
PubMed: 28434655
DOI: 10.1016/j.biopsych.2017.03.003 -
Trends in Endocrinology and Metabolism:... Aug 2023Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E... (Review)
Review
Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.
Topics: Humans; Neurodegenerative Diseases; Lipid Metabolism; Apolipoproteins E; Phenotype; Alzheimer Disease
PubMed: 37357100
DOI: 10.1016/j.tem.2023.05.002 -
Neuron Jan 2021Apolipoprotein E (ApoE) is of great interest due to its role as a cholesterol/lipid transporter in the central nervous system (CNS) and as the most influential genetic... (Review)
Review
Apolipoprotein E (ApoE) is of great interest due to its role as a cholesterol/lipid transporter in the central nervous system (CNS) and as the most influential genetic risk factor for Alzheimer disease (AD). Work over the last four decades has given us important insights into the structure of ApoE and how this might impact the neuropathology and pathogenesis of AD. In this review, we highlight the history and progress in the structural and molecular understanding of ApoE and discuss how these studies on ApoE have illuminated the physiology of ApoE, receptor binding, and interaction with amyloid-β (Aβ). We also identify future areas of study needed to advance our understanding of how ApoE influences neurodegeneration.
Topics: Alzheimer Disease; Animals; Apolipoproteins E; Brain; Humans; Protein Multimerization; Protein Structure, Secondary; Protein Transport; Receptors, LDL
PubMed: 33176118
DOI: 10.1016/j.neuron.2020.10.008 -
Pathology Feb 2019Apolipoprotein E (apoE), a 34 kDa circulating glycoprotein of 299 amino acids, predominantly synthesised in the liver, associates with triglyceride-rich lipoproteins to... (Review)
Review
Apolipoprotein E (apoE), a 34 kDa circulating glycoprotein of 299 amino acids, predominantly synthesised in the liver, associates with triglyceride-rich lipoproteins to mediate the clearance of their remnants after enzymatic lipolysis in the circulation. Its synthesis in macrophages initiates the formation of high density-like lipoproteins to effect reverse cholesterol transport to the liver. In the nervous system apoE forms similar lipoproteins which perform the function of distributing lipids amongst cells. ApoE accounts for much of the variation in plasma lipoproteins by three common variants (isoforms) that influence low-density lipoprotein concentration and the risk of atherosclerosis. ApoE2 generally is most favourable and apoE4 least favourable for cardiovascular and neurological health. The apoE variants relate to different amino acids at positions 112 and 158: cysteine in both for apoE2, arginine at both sites for apoE4, and respectively cysteine and arginine for apoE3 that is viewed as the wild type. Paradoxically, under metabolic stress, homozygosity for apoE2 may result in dysbetalipoproteinaemia in adults owing to impaired binding of remnant lipoproteins to the LDL receptor and related proteins as well as heparan sulphate proteoglycans. This highly atherogenic condition is also seen with other mutations in apoE, but with autosomal dominant inheritance. Mutations in apoE may also cause lipoprotein glomerulopathy. In the central nervous system apoE binds amyloid β-protein and tau protein and fragments may incur cellular damage. ApoE4 is a strong risk factor for the development of Alzheimer's disease. ApoE has several other physiological effects that may influence health and disease, including supply of docosahexaenoic acid for the brain and modulating immune and inflammatory responses. Genotyping of apoE may have application in disorders of lipoprotein metabolism as well as glomerulopathy and may be relevant to personalised medicine in understanding cardiovascular risk, and the outcome of nutritional and therapeutic interventions. Quantitation of apoE will probably not be clinically useful. ApoE is also of interest as it may generate peptides with biological function and could be employed in nanoparticles that may allow crossing of the blood-brain barrier. Therapeutic options may emerge from these newer insights.
Topics: Amyloid beta-Peptides; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Cardiovascular Diseases; Dyslipidemias; Health; Heparan Sulfate Proteoglycans; Humans; Lipid Metabolism; Lipoproteins; Liver; Nervous System; Protein Isoforms; Receptors, LDL; Risk Factors
PubMed: 30598326
DOI: 10.1016/j.pathol.2018.11.002 -
Neurobiology of Disease Dec 2014Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms... (Review)
Review
Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. These receptors internalize apoE-containing lipoprotein particles; thus, apoE participates in the distribution/redistribution of lipids among various tissues and cells of the body. In addition, intracellular apoE may modulate various cellular processes physiologically or pathophysiologically, including cytoskeletal assembly and stability, mitochondrial integrity and function, and dendritic morphology and function. Elucidation of the functional domains within this protein and of the three-dimensional structure of the major isoforms of apoE has contributed significantly to our understanding of its physiological and pathophysiological roles at a molecular level. It is likely that apoE, with its multiple cellular origins and multiple structural and biophysical properties, is involved widely in processes of lipid metabolism and neurobiology, possibly encompassing a variety of disorders of neuronal repair, remodeling, and degeneration by interacting with different factors through various pathways.
Topics: Alzheimer Disease; Animals; Apolipoproteins E; Brain; Disease Models, Animal; Humans; Lipid Metabolism; Mice; Protein Binding
PubMed: 25173806
DOI: 10.1016/j.nbd.2014.08.025 -
Neuron Apr 2022The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions,... (Review)
Review
The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel "ApoE Cascade Hypothesis" in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.
Topics: Alzheimer Disease; Amino Acids; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Humans; Protein Isoforms
PubMed: 35298921
DOI: 10.1016/j.neuron.2022.03.004 -
Neuron Feb 2024Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the...
Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
Topics: Mice; Animals; Apolipoprotein E4; Apolipoprotein E3; Apolipoproteins E; Tauopathies; Cholesterol; Alzheimer Disease; Mice, Transgenic
PubMed: 37995685
DOI: 10.1016/j.neuron.2023.10.023