Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

Current Opinion in Lipidology - Tập 28 Số 1 - Trang 60-67 - 2017
Fan Liao1, Hyejin Yoon2,3, Jungsu Kim2,3,4
1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
2Department of Neuroscience Mayo Clinic Jacksonville Florida USA
3Neurobiology of Disease Graduate Program, Mayo Graduate School
4to Dr Jungsu Kim, Assistant Professor, Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road S., Jacksonville, FL 32224, USA. Tel: +1 904 953 2652

Tóm tắt

Purpose of review APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. Recent findings ApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis. Summary Emerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.

Từ khóa


Tài liệu tham khảo

Selkoe, 2016, The amyloid hypothesis of Alzheimer's disease at 25 years, EMBO Mol Med, 8, 595, 10.15252/emmm.201606210

Sevigny, 2016, The antibody aducanumab reduces Aβ plaques in Alzheimer's disease, Nature, 537, 50, 10.1038/nature19323

Huang, 2014, Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases, Neurobiol Dis, 72, 3, 10.1016/j.nbd.2014.08.025

Kim, 2009, The role of apolipoprotein E in Alzheimer's disease, Neuron, 63, 287, 10.1016/j.neuron.2009.06.026

Castellano, 2011, Human apoE isoforms differentially regulate brain amyloid-β peptide clearance, Sci Transl Med, 3, 89ra57, 10.1126/scitranslmed.3002156

Koldamova, 2014, ATP-binding cassette transporter A1: from metabolism to neurodegeneration, Neurobiol Dis, 72, 13, 10.1016/j.nbd.2014.05.007

Yassine, 2016, ABCA1-mediated cholesterol efflux capacity to cerebrospinal fluid is reduced in patients with mild cognitive impairment and Alzheimer's disease, J Am Heart Assoc, 5, e002886, 10.1161/JAHA.115.002886

Nordestgaard, 2015, Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease, Alzheimers Dement, 11, 1430, 10.1016/j.jalz.2015.04.006

Yoon, 2016, MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease, Biochim Biophys Acta, 1861, 2139, 10.1016/j.bbalip.2016.04.020

Martinez-Morillo, 2014, Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls, Acta Neuropathol, 127, 633, 10.1007/s00401-014-1266-2

Wildsmith, 2012, In vivo human apolipoprotein E isoform fractional turnover rates in the CNS, PLoS One, 7, e38013, 10.1371/journal.pone.0038013

Toledo, 2014, CSF Apo-E levels associate with cognitive decline and MRI changes, Acta Neuropathol, 127, 621, 10.1007/s00401-013-1236-0

Nam, 2016, RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Abeta oligomers, Sci Rep, 6, 24048, 10.1038/srep24048

Habchi, 2016, An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Abeta42 aggregates linked with Alzheimer's disease, Sci Adv, 2, e1501244, 10.1126/sciadv.1501244

Dai, 2016, Liver X receptors regulate cerebrospinal fluid production, Mol Psychiatry, 21, 844, 10.1038/mp.2015.133

Kim, 2015, microRNA-33 regulates ApoE lipidation and amyloid-beta metabolism in the brain, J Neurosci, 35, 14717, 10.1523/JNEUROSCI.2053-15.2015

Basak, 2012, Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes, J Biol Chem, 287, 13959, 10.1074/jbc.M111.288746

Han, 2016, Amyloid beta-interacting partners in Alzheimer's disease: from accomplices to possible therapeutic targets, Prog Neurobiol, 137, 17, 10.1016/j.pneurobio.2015.12.004

Choi, 2015, The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Abeta amyloidosis, Sci Transl Med, 7, 10.1126/scitranslmed.aad1904

Tamboli, 2014, Extracellular proteolysis of apolipoprotein E (apoE) by secreted serine neuronal protease, PLoS One, 9, e93120, 10.1371/journal.pone.0093120

Suenaga, 2015, Monocytic elastase-mediated apolipoprotein-E degradation: potential involvement of microglial elastase-like proteases in apolipoprotein-E proteolysis in brains with Alzheimers disease, Biochim Biophys Acta, 1854, 1010, 10.1016/j.bbapap.2015.04.028

Chu, 2016, HtrA1 proteolysis of ApoE in vitro is allele selective, J Am Chem Soc, 138, 9473, 10.1021/jacs.6b03463

Tai, 2016, The role of APOE in cerebrovascular dysfunction, Acta Neuropathol, 131, 709, 10.1007/s00401-016-1547-z

Nelson, 2013, APOE-epsilon2 and APOE-epsilon4 correlate with increased amyloid accumulation in cerebral vasculature, J Neuropathol Exp Neurol, 72, 708, 10.1097/NEN.0b013e31829a25b9

Yu, 2015, APOE and cerebral amyloid angiopathy in community-dwelling older persons, Neurobiol Aging, 36, 2946, 10.1016/j.neurobiolaging.2015.08.008

Serrano-Pozo, 2015, APOEepsilon2 is associated with milder clinical and pathological Alzheimer disease, Ann Neurol, 77, 917, 10.1002/ana.24369

Bien-Ly, 2015, Lack of widespread BBB disruption in Alzheimer's disease models: focus on therapeutic antibodies, Neuron, 88, 289, 10.1016/j.neuron.2015.09.036

Sperling, 2012, Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis, Lancet Neurol, 11, 241, 10.1016/S1474-4422(12)70015-7

Sakai, 2014, Abeta immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy, Acta Neuropathol, 128, 777, 10.1007/s00401-014-1340-9

Wisniewski, 1992, Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid, Neurosci Lett, 135, 235, 10.1016/0304-3940(92)90444-C

Thal, 2010, Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's disease, Acta Neuropathol, 120, 169, 10.1007/s00401-010-0707-9

Fryer, 2005, Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model, J Neurosci, 25, 2803, 10.1523/JNEUROSCI.5170-04.2005

Oddo, 2009, Genetically altering Abeta distribution from the brain to the vasculature ameliorates tau pathology, Brain Pathol, 19, 421, 10.1111/j.1750-3639.2008.00194.x

Liao, 2015, Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models, Acta Neuropathol Commun, 3, 70, 10.1186/s40478-015-0250-y

Tai, 2015, APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective, J Neurochem, 133, 465, 10.1111/jnc.13072

Chakrabarty, 2015, IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior, Neuron, 85, 519, 10.1016/j.neuron.2014.11.020

Ulrich, 2016, TREM2 function in Alzheimer's disease and neurodegeneration, ACS Chem Neurosci, 7, 420, 10.1021/acschemneuro.5b00313

Yuan, 2016, TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy, Neuron, 90, 724, 10.1016/j.neuron.2016.05.003

Wang, 2016, TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques, J Exp Med, 213, 667, 10.1084/jem.20151948

Yeh, 2016, TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia, Neuron, 91, 328, 10.1016/j.neuron.2016.06.015

Atagi, 2015, Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2), J Biol Chem, 290, 26043, 10.1074/jbc.M115.679043

Bailey, 2015, The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E, J Biol Chem, 290, 26033, 10.1074/jbc.M115.677286

Li, 2015, Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia, FASEB J, 29, 1754, 10.1096/fj.14-262683

Heinsinger, 2016, Apolipoprotein E genotype affects size of ApoE complexes in cerebrospinal fluid, J Neuropathol Exp Neurol, 75, 918, 10.1093/jnen/nlw067

Lee, 2016, Neurometabolic roles of ApoE and Ldl-R in mouse brain, J Bioenerg Biomembr, 48, 13, 10.1007/s10863-015-9636-6

Zhu, 2015, Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis, Proc Natl Acad Sci U S A, 112, 11965, 10.1073/pnas.1510011112

Salameh, 2016, Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease, Exp Biol Med (Maywood), 241, 1676, 10.1177/1535370216660770

Chan, 2015, Differential interaction of apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice, Sci Rep, 5, 13842, 10.1038/srep13842

Chan, 2016, ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Abeta impairment of insulin signaling in an Alzheimer's disease mouse model, Sci Rep, 6, 26119, 10.1038/srep26119

Kim, 2014, Apolipoprotein E in synaptic plasticity and Alzheimer's disease: potential cellular and molecular mechanisms, Mol Cells, 37, 767, 10.14348/molcells.2014.0248

Chung, 2016, Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes, Proc Natl Acad Sci U S A, 113, 10186, 10.1073/pnas.1609896113

Gillespie, 2016, Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples, Neuron, 90, 740, 10.1016/j.neuron.2016.04.009

Theendakara, 2016, Direct transcriptional effects of apolipoprotein E, J Neurosci, 36, 685, 10.1523/JNEUROSCI.3562-15.2016

Sen, 2015, ApoE4 and abeta oligomers reduce BDNF expression via HDAC nuclear translocation, J Neurosci, 35, 7538, 10.1523/JNEUROSCI.0260-15.2015

Thông tin
Thông tin xuất bản

Current Opinion in Lipidology

Tập 28 Số 1

60-67

Thông tin tác giả