Alzheimer's Disease; Apoe; RNAi; neurodegeneration; oligonucleotide therapeutics; siRNA; RNA, Small Interfering; Apolipoproteins E; Apolipoprotein E4; Amyloid; Amyloidogenic Proteins; Amyloid beta-Peptides; Mice; Animals; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Apolipoproteins E/genetics; Apolipoproteins E/metabolism; Apolipoprotein E4/genetics; Amyloid/metabolism; Brain/pathology; Amyloidogenic Proteins/metabolism; Amyloid beta-Peptides/metabolism; Mice, Transgenic; Alzheimer Disease/pathology; Brain; Epidemiology; Health Policy; Developmental Neuroscience; Neurology (clinical); Geriatrics and Gerontology; Cellular and Molecular Neuroscience; Psychiatry and Mental Health
Abstract :
[en] [en] INTRODUCTION: The most significant genetic risk factor for late-onset Alzheimer's disease (AD) is APOE4, with evidence for gain- and loss-of-function mechanisms. A clinical need remains for therapeutically relevant tools that potently modulate APOE expression.
METHODS: We optimized small interfering RNAs (di-siRNA, GalNAc) to potently silence brain or liver Apoe and evaluated the impact of each pool of Apoe on pathology.
RESULTS: In adult 5xFAD mice, siRNAs targeting CNS Apoe efficiently silenced Apoe expression and reduced amyloid burden without affecting systemic cholesterol, confirming that potent silencing of brain Apoe is sufficient to slow disease progression. Mechanistically, silencing Apoe reduced APOE-rich amyloid cores and activated immune system responses.
DISCUSSION: These results establish siRNA-based modulation of Apoe as a viable therapeutic approach, highlight immune activation as a key pathway affected by Apoe modulation, and provide the technology to further evaluate the impact of APOE silencing on neurodegeneration.
Disciplines :
Neurology
Author, co-author :
Ferguson, Chantal M ; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Hildebrand, Samuel; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Godinho, Bruno M D C; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Buchwald, Julianna; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Echeverria, Dimas; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Coles, Andrew; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Grigorenko, Anastasia; Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Vangjeli, Lorenc; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Sousa, Jacquelyn; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
McHugh, Nicholas; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Hassler, Matthew; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Santarelli, Francesco; Luxembourg Centre for Systems Biomedicine (LCSB), Esch-sur-Alzette, Luxembourg
HENEKA, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; Luxembourg Centre for Systems Biomedicine (LCSB), Esch-sur-Alzette, Luxembourg
Rogaev, Evgeny; Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Khvorova, Anastasia; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
We would like to thank Dr Arya Biragyn, NIA, for gifting us AD mouse strains, and the Animal Medicine Group at UMass Chan Medical School. We would like to thank Emily Haberlin and Darryl Conte for editing the manuscript. This work was supported by NS 104022, GM-131839, S10 OD020012, and ADDF 20170101/Rogaev; National Research Service Award 1F30AG066373-01, and T32GM107000.We would like to thank Dr Arya Biragyn, NIA, for gifting us AD mouse strains, and the Animal Medicine Group at UMass Chan Medical School. We would like to thank Emily Haberlin and Darryl Conte for editing the manuscript. This work was supported by NS 104022, GM\u2010131839, S10 OD020012, and ADDF 20170101/Rogaev; National Research Service Award 1F30AG066373\u201001, and T32GM107000.
Qaseem A, Snow V. Owens, and the Joint American College of Physicians/American Academy of Family Physicians Panel on dementia. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American academy of family physicians. Ann Intern Med. 2008;148:370-378.
Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease. JAMA. 2003;289:210-216.
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E Type 4 Allele and the risk fo Alzheimer's disease in late onset families. Science. 1993;261:921-923.
Frisoni GB, Govoni S, Geroldi C, et al. Gene dose of the E4 Allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer's disease. Ann Neurol. 1995;37:596-604.
Karch CM, Goate AM. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77:43-51.
Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH. Lipoproteins and their receptors in the central nervous system. J Biol Chem. 1987;262:14352-14360.
Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green flourescent protein gene to teh ApoE locus. Neurobiol Dis. 2006;26:4985-4994.
Michael S, Brown JLG. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34-47.
David M, Holtzman KRB, Tenkova T, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci. 2000;97:2892-2897.
David M, Holtzman KRB, Wu S, et al. Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease. J Clin Invest. 1999;103:15-21.
Kim J, Jiang H, Park S, et al. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J Neurosci. 2011;31:18007-18012.
Bales KR, Verina T, Dodel RC, et al. Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat Genet. 1997;17:263-264.
Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesionsinmicelackingapolipoproteinE. Science. 1992;258:468-471.
Lane-Donovan C, Wong WM, Durakoglugil MS, et al. Genetic restoration of plasma ApoE improves cognition and partially restores synaptic defects in ApoE-deficient mice. J Neurosci. 2016;36:10141-10150.
Huynh TV, Wang C, Tran AC, et al. Lack of hepatic apoE does not influence early Abeta deposition: observations from a new APOE knock-in model. Mol Neurodegener. 2019;14:37.
Huynh TV, Liao F, Francis CM, et al. Age-dependent effects of apoe reduction using antisense oligonucleotides in a model of beta-amyloidosis. Neuron. 2017;96:1013-1023. e4.
Litvinchuk A, Huynh TPV, Shi Y, et al. Apolipoprotein E4 reduction with antisense oligonucleotides decreases neurodegeneration in a tauopathy model. Ann Neurol. 2021;89(5):952-966.
Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017;35:238-248.
Akinc A, Querbes W, De S, et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 2010;18:1357-1364.
Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136:16958-16961.
Nair JK, Attarwala H, Sehgal A, et al. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates. Nucleic Acids Res. 2017;45:10969-10977.
Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376:1430-1440.
Alterman JF, Godinho B, Hassler MR, et al. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat Biotechnol. 2019;37:884-894.
Sharma VK, Osborn MF, Hassler MR, et al. Novel cluster and monomer-based GalNAc structures induce effective uptake of siRNAs in vitro and in vivo. Bioconjug Chem. 2018;29:2478-2488.
Haraszti RA, Roux L, Coles AH, et al. 5΄-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo. Nucleic Acids Res. 2017;45:7581-7592.
Gentalen ET, Proctor JM. Using the peggy simple western system for fine needle aspirate analysis. Methods Mol Biol. 2015;1219:139-155. doi:10.1007/978-1-4939-1661-0_11
Venegas C, Kumar S, Franklin BS, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017;552:355-361.
Liu C, Desikan R, Ying Z, et al. Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model. PLoS One. 2012;7:e50767.
Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15-21.
Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinf. 2011;12:323.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Zhu A, Ibrahim JG, Love MI. Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. Bioinformatics. 2019;35:2084-2092.
Gennady K, Vladimir S, Nikolay B, Boris S, Maxim NA, Alexey S. Fast gene set enrichment analysis. bioRxiv. 2021:060012.
Brionne A, Juanchich A, Hennequet-Antier C. ViSEAGO: a bioconductor package for clustering biological functions using gene ontology and semantic similarity. BioData Mining. 2019;12:16.
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinf. 2008;9:559.
Zhang Y, Parmigiani G, Johnson WE. ComBat-seq: batch effect adjustment for RNA-seq count data. NAR Genom Bioinform. 2020;2:lqaa078.
Botía JA, Vandrovcova J, Forabosco P, et al. An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks. BMC Syst Biol. 2017;11:47.
Kolberg L, Raudvere U, Kuzmin I, Vilo J, Peterson H. gprofiler2 – an R package for gene list functional enrichment analysis and namespace conversion toolset g:profiler. F1000Research. 2020;9:709.
Mathys H, Adaikkan C, Gao F, et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 2017;21:366-380.
Hasel P, Rose IVL, Sadick JS, Kim RD, Liddelow SA. Neuroinflammatory astrocyte subtypes in the mouse brain. Nat Neurosci. 2021;24(10):1475-1487.
Fitz NF, Nam KN, Wolfe CM, et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease. Nat Commun. 2021;12:3416.
Grubman A, Choo XY, Chew G, et al. Transcriptional signature in microglia associated with Abeta plaque phagocytosis. Nat Commun. 2021;12:3015.
Roopra A. MAGIC: a tool for predicting transcription factors and cofactors driving gene sets using ENCODE data. PLoS Comput Biol. 2020;16:e1007800.
Sala Frigerio C, Wolfs L, Fattorelli N, et al. The major risk factors for Alzheimer's disease: age, sex, and genes modulate the microglia response to abeta plaques. Cell Rep. 2019;27:1293-1306 e6.
Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36:411-420.
Ferguson CM, Echeverria D, Hassler M, Ly S, Khvorova A. Cell type impacts accessibility of mRNA to silencing by RNA interference. Mol Ther Nucleic Acids. 2020;21:384-393.
Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, et al. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis. 2006;24:516-524.
Jankowsky JLSH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Engineering. 2001;16:157-165.
Jankowsky JL, Fadale DJ, Anderson J, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004;13:159-170.
Ikonomovic MD, Abrahamson EE, Isanski BA, et al. X-34 labeling of abnormal protein aggregates during the progression of Alzheimer's disease Methods Enzymol. 2006;412:123-144. doi:10.1016/S0076-6879(06)12009-1
Ordonez-Gutierrez L, Fernandez-Perez I, Herrera JL, Anton M, Benito-Cuesta I, Wandosell F. AbetaPP/PS1 transgenic mice show sex differences in the cerebellum associated with aging. J Alzheimers Dis. 2016;54:645-656.
Gu L, Guo Z. Alzheimer's Abeta42 and Abeta40 peptides form interlaced amyloid fibrils. J Neurochem. 2013;126:305-311.
Esparza TJ, Wildburger NC, Jiang H, et al. Soluble amyloid-beta aggregates from human Alzheimer's disease brains. Sci Rep. 2016;6:38187.
Han S, Kollmer M, Markx D, Claus S, Walther P, Fandrich M. Amyloid plaque structure and cell surface interactions of beta-amyloid fibrils revealed by electron tomography. Sci Rep. 2017;7:43577.
Oakley H, Cole SL, Logan S, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129-10140.
Youmans KL, Tai LM, Kanekiyo T, et al. Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody. Mol Neurodegener. 2012;7:8.
Kummer MP, Heneka MT. Truncated and modified amyloid-beta species. Alzheimers Res Ther. 2014;6:28.
Miners JS, Barua N, Kehoe PG, Gill S, Love S. Aβ-Degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol. 2011;70:944-959.
Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of β-Amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40:1087-1093.
Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med. 2012;2:a006270.
Kiskis J, Fink H, Nyberg L, Thyr J, Li JY, Enejder A. Plaque-associated lipids in Alzheimer's diseased brain tissue visualized by nonlinear microscopy. Sci Rep. 2015;5:13489.
Hashimoto T, Serrano-Pozo A, Hori Y, et al. Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid Peptide. J Neurosci. 2012;32:15181-15192.
Meilandt WJ, Ngu H, Gogineni A, et al. Trem2 deletion reduces late-stage Amyloid plaque accumulation, elevates the Abeta42:abeta40 Ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2APP Alzheimer's mouse model. J Neurosci. 2020;40:1956-1974.
Parhizkar S, Arzberger T, Brendel M, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019;22:191-204.
Ulrich JD, Ulland TK, Mahan TE, et al. ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med. 2018;215:1047-1058.
Stephen TL, Cacciottolo M, Balu D, et al. APOE genotype and sex affect microglial interactions with plaques in Alzheimer's disease mice. Acta Neuropathol Commun. 2019;7:82.
Fitz NF, Wolfe CM, Playso BE, et al. Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol Neurodegener. 2020;15:41.
Rapic S, Backes H, Viel T, et al. Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease. Neurobiol Aging. 2013;34:351-354.
Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005;5:375-386.
Pandey RS, Graham L, Uyar A, Preuss C, Howell GR, Carter GW. Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer's disease. Mol Neurodegener. 2019;14:50.
Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549:523-527.
Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017;169:1276-1290 e17.
Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: aPOE and TREM2 in the spotlight. Nat Rev Immunol. 2018;18:759-772.
Chung WS, Verghese PB, Chakraborty C, et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci USA. 2016;113:10186-10191.
Lewis TL, Cao D, Lu H, et al. Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. J Biol Chem. 2010;285:36958-36968.
Lefterov I, Fitz NF, Cronican AA, et al. Apolipoprotein A-I deficiency increases cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice. J Biol Chem. 2010;285:36945-36957.
Androvic P, Kirdajova D, Tureckova J, et al. Decoding the transcriptional response to ischemic stroke in young and aged mouse brain. Cell Rep. 2020;31:107777.
Hernandez-Ortega K, Garcia-Esparcia P, Gil L, Lucas JJ, Ferrer I. Altered machinery of protein synthesis in Alzheimer's: from the nucleolus to the ribosome. Brain Pathol. 2016;26:593-605.
Yu JT, Tan L, Hardy J. Apolipoprotein E in Alzheimer's disease: an update. Annu Rev Neurosci. 2014;37:79-100.
Hardy J, Escott-Price V. Genes, pathways and risk prediction in Alzheimer's disease. Hum Mol Genet. 2019;28:R235-R240.
Williams T, Borchelt DR, Chakrabarty P. Therapeutic approaches targeting Apolipoprotein E function in Alzheimer's disease. Mol Neurodegener. 2020;15:8.
Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501-518.
Brown CR, Gupta S, Qin J, et al. Investigating the pharmacodynamic durability of GalNAc-siRNA conjugates. Nucleic Acids Res. 2020;48(21):11827-11844.
Giannisis A, Patra K, Edlund AK, et al. Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice. Mol Psychiatry. 2022;27(8):3533-3543.
Krasemann S, Madore C, Cialic R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47:566-581 e9.
Wan YW, Al-Ouran R, Mangleburg CG, et al. Meta-Analysis of the Alzheimer's disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 2020;32:107908.
Wang N, Wang M, Jeevaratnam S, et al. Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination. Molecular Neurodegeneration. 2022;17:75.
Friker LL, Scheiblich H, Hochheiser IV, et al. β-Amyloid Clustering around ASC fibrils boosts its toxicity in microglia. Cell Rep. 2020;30:3743-3754. e6.
Pascoal TA, Benedet AL, Ashton NJ, et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med. 2021;27:1592-1599.
Wang H, Kulas JA, Wang C, Holtzman DM, Ferris HA, Hansen SB. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. Proc Natl Acad Sci USA. 2021;118:e2102191118.
Ye S, Huang Y, Mullendorff K, et al. Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proc Natl Acad Sci USA. 2005;102:18700-18705.
Paradise V, Sabu M, Bafia J, et al. ApoE isoforms differentially regulate neuronal membrane proteasomes to shift the threshold for pathological aggregation of endogenous Tau. Biorxiv. 2022:20221129518293.
Liao F, Zhang TJ, Jiang H, et al. 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. 2015;3:70.
Caesar I, Nilsson KPR, Hammarstrom P, et al. ApoE Alzheimer's Disease Aβ-amyloid plaque morphology varies according to APOE isotype. Research Square Platform LLC. 2023:rs.3.rs-2524641.
Farrer LA, Cupples LA, Haines JL, et al, for the APOE and Alzheimer Disease Meta Analysis Consortium. Effects of age, sex, and ethnicity on the association between Apolipoprotein E genotype and Alzheimer disease. JAMA. 1997;278:1349-1356.
Osuntokun BO, Sahota A, Ogunniyi AO, et al. Lack of an association between the E4 allele of ApoE and Alzheimer's disease in elderly Nigerians. Ann Neurol. 1995;38:463-465.
Tang MX, Maestre G, Tsai WY, et al. Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. Am J Hum Genet. 1996;58:574-584.
Reitz C, Mayeux R. Genetics of Alzheimer's disease in Caribbean Hispanic and African American populations. Biol Psychiatry. 2014;75:534-541.
Reiman EM, Arboleda-Velasquez JF, Quiroz YT, et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5000-person neuropathological study. Nat Commun. 2020;11:667.
Arboleda-Velasquez JF, Lopera F, O'Hare M, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25:1680-1683.
Mauch DH, Nägler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001;294:1354-1357.
Kim J, Basak JM, Holtzman DM. The Role of Apolipoprotein E in Alzheimer's Disease. Neuron. 2009;63:287-303.
Lohse P, Brewer HB 3rd, Meng MS, Skarlatos SI, LaRosa JC. Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res. 1992;33:1583-1590.
Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71:1228-1236.
Huang YA, Zhou B, Nabet AM, Wernig M, Südhof TC. Differential signaling mediated by ApoE2, ApoE3, and ApoE4 in human neurons parallels Alzheimer's disease risk. J Neurosci. 2019;39:7408-7427.
Weisgraber KH, Innerarity TL, Mahley RW. Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem. 1982;257:2518-2521.
Bu G. APOE targeting strategy in Alzheimer's disease: lessons learned from protective variants. Mol Neurodegener. 2022;17:51.
Janus C, Flores AY, Xu G, Borchelt DR. Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol Aging. 2015;36:2519-2532.
Savonenko A, Xu GM, Melnikova T, et al. Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis. 2005;18:602-617.
Devi L, Ohno M. Mitochondrial dysfunction and accumulation of the β-secretase-cleaved C-terminal fragment of APP in Alzheimer's disease transgenic mice. Neurobiol Dis. 2012;45:417-424.
