An emerging role of neuronal Apolipoprotein E in the pathogenesis of Alzheimer's disease

Xianglong HOU, Yelin CHEN

Chinese Journal of Alzheimer's Disease and Related Disorders ›› 2025, Vol. 8 ›› Issue (1) : 54-60.

PDF(1039 KB)
Home Journals Chinese Journal of Alzheimer's Disease and Related Disorders
Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

About  /  Aim & scope  /  Editorial board  /  Indexed  /  Contact  / 
PDF(1039 KB)
Chinese Journal of Alzheimer's Disease and Related Disorders ›› 2025, Vol. 8 ›› Issue (1) : 54-60. DOI: 10.3969/j.issn.2096-5516.2025.01.008

An emerging role of neuronal Apolipoprotein E in the pathogenesis of Alzheimer's disease

Author information +
History +

Abstract

Different isoforms of Apolipoprotein E (ApoE) lead to different risks of Alzheimer's disease (AD). ApoE2 reduces the risk of AD, whereas ApoE4 is the main genetic risk factor for AD. The role of glia-secreted ApoE in the pathogenesis of AD has been extensively studied, whereas the contribution of neuronal ApoE remains largely unexplored. Recent studies have found that ApoE is also expressed in neurons, where it plays important roles in the pathogenesis of AD, including regulation of amyloid plaque seeding and growth, phosphorylation of Tau, and neurodegeneration, etc. Based on these studies, a gene therapeutic strategy using adeno-associated virus (AAV) to express ApoE2 in neurons is now in that phase II clinical trials for AD treatment. This article summarizes the knowledge about the emerging role of neuronal ApoE in AD pathogenesis.

Key words

Apolipoprotein E / Alzheimer's disease / Neuron

Cite this article

Download Citations
Xianglong HOU , Yelin CHEN. An emerging role of neuronal Apolipoprotein E in the pathogenesis of Alzheimer's disease[J]. Chinese Journal of Alzheimer's Disease and Related Disorders. 2025, 8(1): 54-60 https://doi.org/10.3969/j.issn.2096-5516.2025.01.008

References

[1]
Toodayan N. Professor alois Alzheimer (1864-1915): lest we forget[J]. J Clin Neurosci, 2016, 31: 47-55.
[2]
Association AS. 2017 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2017, 13: 325-373.
[3]
Chan KY, Wang W, Wu JJ, et al. Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990-2010: a systematic review and analysis[J]. Lancet, 2013, 381(9882): 2016-2023.
[4]
Nichols E, Szoeke CEI, Vollset SE, et al. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the global burden of disease study 2016[J]. Lancet Neurol, 2019, 18(1): 88-106.
[5]
Ying W, Jing Q, Rui H, et al. Alzheimer disease in China (2015-2050) estimated using the 1% population sampling survey in 2015[J]. China Journal of Alzheimer's Disease and Related Disorders, 2019, 2.
[6]
任汝静, 殷鹏, 王志会, 等. 中国阿尔茨海默病报告2021[J]. 2021, 20(4): 21.
[7]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics[J]. Sci, 2002, 297(5580): 353-356.
[8]
Serrano-pozo A, Frosch MP, Masliah E, et al. Neuropathological alterations in Alzheimer disease[J]. Cold Spring Harb Perspect Med, 2011, 1(1): a006189.
[9]
Fazeli E, Child DD, Bucks SA, et al. A familial missense variant in the Alzheimer's disease gene SORL1 impairs its maturation and endosomal sorting[J]. Acta Neuropathologica, 2024, 147(1): 20.
[10]
Zhang C, Wu B, Beglopoulos V, et al. Presenilins are essential for regulating neurotransmitter release[J]. Nat, 2009, 460(7255): 632-636.
[11]
Vetrivel KS, Barman A, Chen Y, et al. Loss of cleavage at beta'-site contributes to apparent increase in beta-amyloid peptide (Abeta) secretion by beta-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein[J]. J Biol Chem, 2011, 286(29): 26166-26177.
[12]
Khanahmadi M, Farhud DD, Malmir M, et al. Genetic of Alzheimer’s disease: a narrative review article[J]. Iran J Pub Heal, 2015, 44(7): 892-901.
[13]
Zhou L, Brouwers N, Benilova I, et al. Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation[J]. EMBO Molecular Med, 2011, 3(5): 291-302.
[14]
Sun L, Zhou R, Yang G, et al. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase[J]. Proc National Acad Sci U S A, 2017, 114(4): E476-e485.
[15]
Chen J, Li Q, Wang J, et al. Topsology of human apolipoprotein E3 uniquely regulates its diverse biological functions[J]. Proc Natl Acad Sci U S A, 2011, 108(36): 14813-14818.
[16]
Reiman EM, Arboleda-Velasquez JF, Quiroz YT, et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study[J]. Nat Commun, 2020, 11(1): 667.
[17]
Yamazaki Y, Zhao N, Caulfield TR, et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies[J]. Nat Review Neurol, 2019, 15(9): 501-518.
[18]
Belloy ME, Andrews SJ, Le Guen Y, et al. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry[J]. JAMA Neurol, 2023, 80(12): 1284-1294.
[19]
Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases[J]. Neurobiol Dis, 2014, 72 Pt A: 3-12.
[20]
Fortea J, Pegueroles J, Alcolea D, et al. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease[J]. Nat Med, 2024, 30(5): 1284-1291.
[21]
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[J]. Nat Med, 2019, 25(11): 1680-1683.
[22]
Medway CW, Abdul-hay S, Mims T, et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease[J]. Mol Neurodegener, 2014, 9: 11.
[23]
Le Guen Y, Belloy ME, Grenier-Boley B, et al. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease[J]. JAMA Neurol, 2022, 79(7): 652-663.
[24]
Guen YL, Belloy ME, Grenier‐Boley B, et al. Rare missense variant (R251G) on APOE counterbalances the Alzheimer's disease risk associated with APOE‐ε4[J]. Alzheimers Dement, 2022, 18.
[25]
Le Guen Y, Raulin AC, Logue MW, et al. Association of african ancestry-specific apoe missense variant R145C with risk of Alzheimer disease[J]. JAMA, 2023, 329(7): 551-560.
[26]
Kanekiyo T, Xu H, Bu G, et al. ApoE and Abeta in Alzheimer's disease: accidental encounters or partners?[J]. Neuron, 2014, 81(4): 740-754.
[27]
Liu CC, Zhao J, Fu Y, et al. Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function[J]. Nat Neurosci, 2022, 25(8): 1020-1033.
[28]
Xu Q, Bernardo A, Walker D, et al. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus[J]. J Neurosci, 2006, 26(19): 4985.
[29]
Zhao N, Liu CC, Qiao W, et al. Apolipoprotein E, receptors, and modulation of Alzheimer's disease[J]. Biological psychiatry, 2017.
[30]
Namba Y, Tomonaga M, Kawasaki H, et al. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in creutzfeldt-jakob disease[J]. Brain Research, 1991, 541,(1): 163-166.
[31]
Huang YA, Zhou B, Wernig M, et al. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion[J]. Cell, 2017, 168(3): 427.
[32]
Christensen DZ, Schneideraxmann T, Lucassen PJ, et al. Accumulation of intraneuronal Aβ correlates with ApoE4 genotype[J]. Acta Neuropathologica, 2010, 119(5): 555-566.
[33]
Hashimoto T, Serranopozo A, Hori Y, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide[J]. J Neurosci, 2012, 32(43): 15181.
[34]
Yu JT, Tan L, Hardy J, et al. Apolipoprotein E in Alzheimer's disease: an update[J]. Annu Rev Neurosci, 2014, 37: 79-100.
[35]
Cerf E, Gustot A, Goormaghtigh E, et al. High ability of apolipoprotein E4 to stabilize amyloid-β peptide oligomers, the pathological entities responsible for Alzheimer's disease[J]. FASEB J, 2011, 25(5): 1585.
[36]
Liu CC, Zhao N, Fu Y, et al. ApoE4 accelerates early seeding of amyloid pathology[J]. Neuron, 2017, 96(5): 1024-1032 e3.
[37]
Huynh TV, Liao F, Francis CM, et al. Age-dependent effects of apoe reduction using antisense oligonucleotides in a model of beta-amyloidosis[J]. Neuron, 2017, 96(5): 1013-1023 e4.
[38]
Lin YT, Seo J, Gao F, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer's disease phenotypes in human iPSC-derived brain cell types[J]. Neuron, 2018, 98(6): 1141-1154.e7.
[39]
Xiong M, Wang C, Gratuze M, et al. Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy[J]. Mol Neurodegener, 2023, 18(1): 17.
[40]
Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates Tau-mediated neurodegeneration in a mouse model of tauopathy[J]. Nature, 2017, 549(7673): 523-527.
[41]
Martens YA, Zhao N, Liu CC, et al. ApoE cascade hypothesis in the pathogenesis of Alzheimer's disease and related dementias[J]. Neuron, 2022, 110(8): 1304-1317.
[42]
Koutsodendris N, Blumenfeld J, Agrawal A, et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits[J]. Nat Aging, 2023, 3(3): 275-296.
[43]
Knoferle J, Yoon SY, Walker D, et al. Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice[J]. J Neurosci, 2014, 34(42): 14069-14078.
[44]
Xu Q, Bernardo A, Walker D, et al. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus[J]. J Neurosci, 2006, 26(19): 4985-4994.
[45]
Zalocusky KA, Najm R, Taubes AL, et al. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease[J]. Nat Neurosci, 2021, 24(6): 786-798.
[46]
Han SH, Hulette C, Saunders AM, et al. Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer's disease and in age-matched controls[J]. Experim Neurol, 1994, 128(1): 13.
[47]
Strittmatter WJ Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease[J]. Proc Nat Acad Sci U S A, 1993, 90(5):1977-1981.
[48]
Metzger RE, Ladu MJ, Pan JB, et al. Neurons of the human frontal cortex display apolipoprotein E immunoreactivity: implications for Alzheimer's disease[J]. J Neuropathol Experiment Neurol, 1996, 55(3): 372-380.
[49]
Zarow C, Victoroff J. Increased apolipoprotein E mRNA in the hippocampus in Alzheimer disease and in rats after entorhinal cortex lesioning[J]. Experiment Neurol, 1998, 149(1): 79-86.
[50]
Xu PT, Gilbert JR, Qiu HL, et al. Specific regional transcription of apolipoprotein E in human brain neurons[J]. A J Path, 1999, 154(2): 601-611.
[51]
Aoki K, Uchihara T, Nakamura A, et al. Expression of apolipoprotein E in ballooned neurons-comparative immunohistochemical study on neurodegenerative disorders and infarction[J]. Acta Neuropathol, 2003, 106(5): 436-440.
[52]
Brecht WJ, Harris FM, Chang S, et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased Tau phosphorylation in brains of transgenic mice[J]. J Neurosci, 2004, 24(10): 2527-2534.
[53]
Belonwu SA, Li Y, Bunis D, et al. Sex-stratified single-cell RNA-seq analysis identifies sex-specific and cell type-specific transcriptional responses in Alzheimer's disease across two brain regions[J]. Mol Neurobiol, 2022, 59(1): 276-293.
[54]
Hou X, Zhang X, Zou H, et al. Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4[J]. Neuron, 2023, 111(12): 1898-1913.e5.
[55]
Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease[J]. Proc Nati Acad Sci U S A, 1993, 90(5): 1977-1981.
[56]
Xia Y, Wang ZH, Zhang J, et al. C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer's disease[J]. Mol Psychiatry, 2021, 26(10): 6002-6022.
[57]
Xu Q, Walker D, Bernardo A, et al. Intron-3 retention/splicing controls neuronal expression of apolipoprotein E in the CNS[J]. J Neurosci, 2008, 28(6): 1452-1459.
[58]
Blumenfeld J, Yip O, Kim MJ, et al. Cell type-specific roles of APOE4 in Alzheimer disease[J]. Nat Rev Neurosci, 2024, 25(2): 91-110.
[59]
Wang C, Najm R, Xu Q, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector[J]. Nat Med, 2018, 24(5): 647-657.
[60]
Jackson RJ, Hyman BT, Serrano-Pozo A, et al. Multifaceted roles of APOE in Alzheimer disease[J]. Nat Rev Neurol, 2024, 20(8):457-474.
[61]
Narasimhan S, Holtzman DM, Apostolova LG, et al. Apolipoprotein E in Alzheimer's disease trajectories and the next-generation clinical care pathway[J]. Nat Neurosci, 2024, 27(7):1236-1252.
[62]
Wadhwani AR, Affaneh A, Van Gulden S, et al. Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in Alzheimer disease[J]. Ann Neurol, 2019, 85(5): 726-739.
[63]
Wang ZH, Xia Y, Wu Z, et al. Neuronal ApoE4 stimulates C/EBPβ activation, promoting Alzheimer's disease pathology in a mouse model[J]. Prog Neurobiol, 2022, 209: 102212.
[64]
Serrano-Pozo A, Das S, Hyman BT, et al. APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches[J]. Lancet Neurol, 2021, 20(1): 68-80.
[65]
Pankiewicz JE, Guridi M, Kim J, et al. Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice[J]. Acta Neuropathologica Communications, 2014, 2: 75.
[66]
Liao F, Hori Y, Hudry E, et al. Anti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis[J]. J Neurosci, 2014, 34(21): 7281-7292.
[67]
Liao F, Li A, Xiong M, et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation[J]. J Clin Invest, 2018, 128(5): 2144-2155.
[68]
Krishnamurthy K, Cantillana V, Wang H, et al. ApoE mimetic improves pathology and memory in a model of Alzheimer's disease[J]. Brain Res, 2020, 1733: 146685.
[69]
Vitek MP, Christensen DJ, Wilcock D, et al. APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer's disease transgenics[J]. Neuro-degener Dis, 2012, 10(1-4): 122-126.
[70]
Ghosal K, Stathopoulos A, Thomas D, et al. The apolipoprotein-E-mimetic COG112 protects amyloid precursor protein intracellular domain-overexpressing animals from Alzheimer's disease-like pathological features[J]. Neurodegener Dis, 2013, 12(1): 51-58.
[71]
Zhao L, Gottesdiener AJ, Parmar M, et al. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models[J]. Neurobiol Aging, 2016, 44: 159-172.
[72]
Rosenberg JB, Kaplitt MG, De BP, et al. AAVrh.10-Mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer's disease[J]. Hum Gene Ther Clin Dev, 2018, 29(1): 24-47.
[73]
Litvinchuk A, Huynh TV, Shi Y, et al. Apolipoprotein E4 reduction with antisense oligonucleotides decreases neurodegeneration in a tauopathy model[J]. Ann Neurol, 2021, 89(5): 952-966.
[74]
Sevigny J, Chiao P, BussiÈre T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease[J]. Nature, 2016, 537(7618): 50-56.
[75]
Wang D, Tai PWL, Gao G, et al. Adeno-associated virus vector as a platform for gene therapy delivery[J]. Nat Rev Drug Discov, 2019, 18(5): 358-378.
[76]
Raguram A, Banskota S, Liu DR, et al. Therapeutic in vivo delivery of gene editing agents[J]. Cell, 2022, 185(15): 2806-2827.
[77]
Gomez Limia C, Baird M, Schwartz M, et al. Emerging perspectives on gene therapy delivery for neurodegenerative and neuromuscular disorders[J]. J Pers Med, 2022, 12(12).

Footnotes

利益冲突声明:所有作者在本研究中均不存在利益冲突。

PDF(1039 KB)

Accesses

Citation

Detail

Sections
Recommended

/