Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling

Alzheimer's & Dementia - Tập 16 Số 9 - Trang 1248-1258 - 2020
Antonino Asaro1, Anne‐Sophie Carlo‐Spiewok1, Anna R. Malik1, Michael Rothe2, Carola G. Schipke3, Oliver Peters4,5, Jöerg Heeren6, Thomas E. Willnow7,1
1Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
2Lipidomix GmbH, Berlin, Germany
3Experimental and Clinical Research Center Charité ‐ Universitätsmedizin Berlin and Berlin Institute of Health Berlin Germany
4Department of Psychiatry, Charité – Universitätsmedizin Berlin, Berlin, Germany
5German Center for Neurodegenerative Diseases, Berlin, Germany
6Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
7Department of Biomedicine, Aarhus University, Aarhus, Denmark

Tóm tắt

AbstractIntroductionApolipoprotein E (apoE) is a carrier for brain lipids and the most important genetic risk factor for Alzheimer's disease (AD). ApoE binds the receptor sortilin, which mediates uptake of apoE‐bound cargo into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk seen with apoE4, but not apoE3, remains unresolved.MethodsCombining neurolipidomics in patient specimens with functional studies in mouse models, we interrogated apoE isoform–specific functions for sortilin in brain lipid metabolism and AD.ResultsSortilin directs the uptake and conversion of polyunsaturated fatty acids into endocannabinoids, lipid‐based neurotransmitters that act through nuclear receptors to sustain neuroprotective gene expression in the brain. This sortilin function requires apoE3, but is disrupted by binding of apoE4, compromising neuronal endocannabinoid metabolism and action.DiscussionWe uncovered the significance of neuronal apoE receptor sortilin in facilitating neuroprotective actions of brain lipids, and its relevance for AD risk seen with apoE4.

Từ khóa


Tài liệu tham khảo

10.1101/cshperspect.a006312

10.1126/science.8346443

10.1038/nrneurol.2012.263

10.1523/JNEUROSCI.2425-12.2013

10.1172/JCI6172

10.1016/j.nbd.2014.08.025

10.1038/nrn3012

10.1016/j.neuron.2004.08.013

10.1523/JNEUROSCI.4225-04.2005

10.1523/JNEUROSCI.0055-07.2007

10.3233/JAD-141635

10.1021/jm960752x

10.1111/bph.13497

10.2174/157015911798376325

10.1038/nrn3820

10.1161/01.ATV.0000201282.64751.47

10.1074/jbc.M409324200

10.1073/pnas.0914984107

10.1007/s00109-014-1152-3

10.1016/j.neuron.2017.09.003

10.1172/JCI25420

10.1001/archneur.63.11.1545

10.1007/BF02536067

10.1038/srep07130

10.1016/j.neurobiolaging.2011.03.012

10.1186/1476-511X-8-2

Maroof N, 2014, Reductions in endocannabinoid levels and enhanced coupling of cannabinoid receptors in the striatum are accompanied by cognitive impairments in the AbetaPPswe/PS1DeltaE9 mouse model of Alzheimer's disease, J Alzheimers Dis, 42, 227, 10.3233/JAD-131961

10.3233/JAD-142349

10.1016/j.celrep.2012.05.001

10.1093/brain/awr046

10.1111/jnc.12255

la Monte SM, 2006, Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease, J Alzheimers Dis, 9, 167, 10.3233/JAD-2006-9209

10.1093/brain/awh452

10.1016/j.expneurol.2006.01.018

10.1126/scitranslmed.aad3650

10.1038/cddis.2014.376

10.1016/j.neurobiolaging.2006.02.012

10.1023/A:1022337519035

10.1111/jnc.14108

Herran E, 2015, Enhanced hippocampal neurogenesis in APP/Ps1 mouse model of Alzheimer's disease after implantation of VEGF‐loaded PLGA Nanospheres, Curr Alzheimer Res, 12, 932, 10.2174/1567205012666151027121622

10.1038/srep02053

10.1074/jbc.M209006200

Xian X, 2018, Reversal of ApoE4‐induced recycling block as a novel prevention approach for Alzheimer's disease, Elife, 7, e40048, 10.7554/eLife.40048

Thông tin
Thông tin xuất bản

Alzheimer's & Dementia

Tập 16 Số 9

1248-1258

Thông tin tác giả