The APOE-TOMM40 Humanized Mouse Model: Characterization of Age, Sex, and PolyT Variant Effects on Gene Expression

Overview

Journal J Alzheimers Dis

Publisher Sage Publications

Specialties Geriatrics
Neurology

Date 2023 Jul 17

PMID 37458041

Authors

William K Gottschalk

Scott Mahon

Dellila Hodgson

Julio Barrera

Delaney Hill

Angela Wei

Manish Kumar

Kathy Dai

Lauren Anderson

Mirta Mihovilovic

Michael W Lutz

Ornit Chiba-Falek

Affiliations

Soon will be listed here.

Abstract

Background: The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer's disease (LOAD) and other age-related conditions.

Objective: Here we developed the first humanized mouse model that contains the entire TOMM40 and APOE genes with all intronic and intergenic sequences including the upstream and downstream regions. Thus, the mouse model carries the human TOMM40 and APOE genes and their intact regulatory sequences.

Methods: We generated the APOE-TOMM40 humanized mouse model in which the entire mouse region was replaced with the human (h)APOE-TOMM40 loci including their upstream and downstream flanking regulatory sequences using recombineering technologies. We then measured the expression of the human TOMM40 and APOE genes in the mice brain, liver, and spleen tissues using TaqMan based mRNA expression assays.

Results: We investigated the effects of the '523' polyT genotype (S/S or VL/VL), sex, and age on the human TOMM40- and APOE-mRNAs expression levels using our new humanized mouse model. The analysis revealed tissue specific and shared effects of the '523' polyT genotype, sex, and age on the regulation of the human TOMM40 and APOE genes. Noteworthy, the regulatory effect of the '523' polyT genotype was observed for all studied organs.

Conclusion: The model offers new opportunities for basic science, translational, and preclinical drug discovery studies focused on the APOE genomic region in relation to LOAD and other conditions in adulthood.

Citing Articles

and variants differentiate the impacts of the 4 allele on Alzheimer's disease risk across sexes, ages, and ancestries.

Kulminski A, Jain-Washburn E, Philipp I, Loika Y, Loiko E, Culminskaya I Alzheimers Dement (Amst). 2024; 16(2):e12600.

PMID: 38912305 PMC: 11193136. DOI: 10.1002/dad2.12600.

References

Gottschalk W, Mihovilovic M, Roses A, Chiba-Falek O . The Role of Upregulated APOE in Alzheimer's Disease Etiology. J Alzheimers Dis Parkinsonism. 2016; 6(1). PMC: 4836841. DOI: 10.4172/2161-0460.1000209. View

Beecham G, Martin E, Li Y, Slifer M, Gilbert J, Haines J . Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet. 2009; 84(1):35-43. PMC: 2668056. DOI: 10.1016/j.ajhg.2008.12.008. View

Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young J . Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019; 570(7761):332-337. PMC: 6865822. DOI: 10.1038/s41586-019-1195-2. View

Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanche H, Junge O . A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals. Mech Ageing Dev. 2011; 132(6-7):324-30. DOI: 10.1016/j.mad.2011.06.008. View

Shao Y, Shaw M, Todd K, Khrestian M, DAleo G, Barnard P . DNA methylation of TOMM40-APOE-APOC2 in Alzheimer's disease. J Hum Genet. 2018; 63(4):459-471. PMC: 6466631. DOI: 10.1038/s10038-017-0393-8. View

Linnertz C, Saucier L, Ge D, Cronin K, Burke J, Browndyke J . Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One. 2009; 4(10):e7480. PMC: 2759540. DOI: 10.1371/journal.pone.0007480. View

Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A . Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. Hum Mol Genet. 2007; 16(8):865-73. DOI: 10.1093/hmg/ddm031. View

Zarow C, Victoroff J . Increased apolipoprotein E mRNA in the hippocampus in Alzheimer disease and in rats after entorhinal cortex lesioning. Exp Neurol. 1998; 149(1):79-86. DOI: 10.1006/exnr.1997.6709. View

Mancera-Paez O, Estrada-Orozco K, Mahecha M, Cruz F, Bonilla-Vargas K, Sandoval N . Differential Methylation in (Chr19; Exon Four; from 44,909,188 to 44,909,373/hg38) and Increased Apolipoprotein E Plasma Levels in Subjects with Mild Cognitive Impairment. Int J Mol Sci. 2019; 20(6). PMC: 6470812. DOI: 10.3390/ijms20061394. View

10.

Mapstone M, Gross T, Macciardi F, Cheema A, Petersen M, Head E . Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome. Alzheimers Dement (Amst). 2020; 12(1):e12028. PMC: 7131985. DOI: 10.1002/dad2.12028. View

11.

Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui S . Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med. 2015; 21(8):880-6. DOI: 10.1038/nm.3913. View

12.

Sullivan P, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick R . Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem. 1997; 272(29):17972-80. DOI: 10.1074/jbc.272.29.17972. View

13.

Martinez-Martinez A, Torres-Perez E, Devanney N, Del Moral R, Johnson L, Arbones-Mainar J . Beyond the CNS: The many peripheral roles of APOE. Neurobiol Dis. 2020; 138:104809. PMC: 7195217. DOI: 10.1016/j.nbd.2020.104809. View

14.

Heinzen E, Need A, Hayden K, Chiba-Falek O, Roses A, Strittmatter W . Genome-wide scan of copy number variation in late-onset Alzheimer's disease. J Alzheimers Dis. 2010; 19(1):69-77. PMC: 2883723. DOI: 10.3233/JAD-2010-1212. View

15.

Kessler K, Giannisis A, Bial G, Foquet L, Nielsen H, Raber J . Behavioral and cognitive performance of humanized APOEε3/ε3 liver mice in relation to plasma apolipoprotein E levels. Sci Rep. 2023; 13(1):1728. PMC: 9889814. DOI: 10.1038/s41598-023-28165-3. View

16.

Tulloch J, Leong L, Thomson Z, Chen S, Lee E, Keene C . Glia-specific APOE epigenetic changes in the Alzheimer's disease brain. Brain Res. 2018; 1698:179-186. PMC: 6388639. DOI: 10.1016/j.brainres.2018.08.006. View

17.

Zheng H, Cai A, Shu Q, Niu Y, Xu P, Li C . Tissue-Specific Metabolomics Analysis Identifies the Liver as a Major Organ of Metabolic Disorders in Amyloid Precursor Protein/Presenilin 1 Mice of Alzheimer's Disease. J Proteome Res. 2018; 18(3):1218-1227. DOI: 10.1021/acs.jproteome.8b00847. View

18.

Zheng J, Sun J, Ji C, Shen L, Chen Z, Xie P . Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer's disease (APP/PS1) mice by inhibiting TGF-β/Smad2/STAT3 signaling. Neurobiol Aging. 2017; 54:112-132. DOI: 10.1016/j.neurobiolaging.2017.03.002. View

19.

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere M . Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009; 41(10):1088-93. PMC: 2845877. DOI: 10.1038/ng.440. View

20.

Babenko V, Afonnikov D, Ignatieva E, Klimov A, Gusev F, Rogaev E . Haplotype analysis of APOE intragenic SNPs. BMC Neurosci. 2018; 19(Suppl 1):16. PMC: 5998902. DOI: 10.1186/s12868-018-0413-4. View