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EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease

2017; Elsevier BV; Volume: 58; Issue: 9 Linguagem: Inglês

10.1194/jlr.r076315

ISSN

1539-7262

Autores

Leon M. Tai, Deebika Balu, Evangelina Ávila-Muñoz, Laila Abdullah, Riya Thomas, N. Collins, Ana C. Valencia‐Olvera, Mary Jo LaDu,

Tópico(s)

Computational Drug Discovery Methods

Resumo

Identified in 1993, APOE4 is the greatest genetic risk factor for sporadic Alzheimer'ns disease (AD), increasing risk up to 15-fold compared with APOE3, with APOE2 decreasing AD risk. However, the functional effects of APOE4 on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)-APOE genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h-APOE rather than mouse (m)-APOE. The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-β (Aβ) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits. EFAD mice were designed as a temporally useful preclinical FAD-Tg-mouse model expressing the h-APOE genotypes for identifying mechanisms underlying APOE-modulated symptoms of AD pathology. From their first description in 2012, EFAD mice have enabled critical basic and therapeutic research. Here we review insights gleaned from the EFAD mice and summarize future directions. Identified in 1993, APOE4 is the greatest genetic risk factor for sporadic Alzheimer'ns disease (AD), increasing risk up to 15-fold compared with APOE3, with APOE2 decreasing AD risk. However, the functional effects of APOE4 on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)-APOE genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h-APOE rather than mouse (m)-APOE. The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-β (Aβ) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits. EFAD mice were designed as a temporally useful preclinical FAD-Tg-mouse model expressing the h-APOE genotypes for identifying mechanisms underlying APOE-modulated symptoms of AD pathology. From their first description in 2012, EFAD mice have enabled critical basic and therapeutic research. Here we review insights gleaned from the EFAD mice and summarize future directions. In humans, Alzheimer'ns disease (AD) progresses over decades, resulting in synaptic dysfunction eventually leading to neuronal loss. Despite the large number of longitudinal aging studies in humans, the lack of cognitive measures coordinated with symptoms of AD pathology results in a poorly understood disease trajectory (1.Erten-Lyons D. Sherbakov L.O. Piccinin A.M. Hofer S.M. Dodge H.H. Quinn J.F. Woltjer R.L. Kramer P.L. Kaye J.A. Review of selected databases of longitudinal aging studies.Alzheimers Dement. 2012; 8: 584-589Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Transgenic (Tg)-mice are a powerful tool to track AD pathology, address mechanistic hypothesis, and assess the activity of potential therapeutics. An overall limitation of all Tg-mouse models is that none reproduce the full spectrum of human AD symptoms and pathology. However, a number of reviews provide specific guidelines for preclinical AD studies with a consistent theme that a useful Tg-mouse model will incorporate major human AD risk factors and demonstrate dysfunction in the AD-relevant symptom of interest (2.Shineman D.W. Basi G.S. Bizon J.L. Colton C.A. Greenberg B.D. Hollister B.A. Lincecum J. Leblanc G.G. Lee L.B. Luo F. et al.Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies.Alzheimers Res. Ther. 2011; 3: 28Crossref PubMed Scopus (81) Google Scholar). Thus, critical to this modeling is the inclusion of the major human AD risk factors. The APOE4 genotype is the greatest genetic risk factor increasing AD risk up to 15-fold compared with the common APOE3 genotype, while APOE2 is protective (3.Reitz C. Mayeux R. Use of genetic variation as biomarkers for mild cognitive impairment and progression of mild cognitive impairment to dementia.J. Alzheimers Dis. 2010; 19: 229-251Crossref PubMed Scopus (41) Google Scholar, 4.Leoni V. The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer's disease.Clin. Chem. Lab. Med. 2011; 49: 375-383Crossref PubMed Google Scholar), but less frequent [estimated: ε2/2 at 0.4%, ε2/3 at 8.8%, and ε2/4 at 1.5% (5.Shinohara M. Kanekiyo T. Yang L. Linthicum D. Shinohara M. Fu Y. Price L. Frisch-Daiello J.L. Han X. Fryer J.D. et al.APOE2 eases cognitive decline during aging: clinical and preclinical evaluations.Ann. Neurol. 2016; (Epub ahead of print. 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APOE and Alzheimer Disease Meta Analysis Consortium.J. Am. Med. Assoc. 1997; 278: 1349-1356Crossref PubMed Google Scholar, 7.Breitner J.C. Wyse B.W. Anthony J.C. Welsh-Bohmer K.A. Steffens D.C. Norton M.C. Tschanz J.T. Plassman B.L. Meyer M.R. Skoog I. et al.APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study.Neurology. 1999; 53: 321-331Crossref PubMed Google Scholar, 8.Martinez M. Campion D. Brice A. Hannequin D. Dubois B. Didierjean O. Michon A. Thomas-Anterion C. Puel M. Frebourg T. et al.Apolipoprotein E epsilon4 allele and familial aggregation of Alzheimer disease.Arch. Neurol. 1998; 55: 810-816Crossref PubMed Scopus (0) Google Scholar, 9.Andersen K. Launer L.J. Dewey M.E. Letenneur L. Ott A. Copeland J.R. Dartigues J.F. Kragh-Sorensen P. Baldereschi M. Brayne C. et al.Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. 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Importantly, oAβ levels in cerebrospinal fluid (CSF) are increased in AD patients versus controls; and are greater with APOE4/4 versus APOE3/3 in AD patients (20.Tai L.M. Bilousova T. Jungbauer L. Roeske S.K. Youmans K.L. Yu C. Poon W.W. Cornwell L.B. Miller C.A. Vinters H.V. et al.Levels of soluble apolipoprotein E/amyloid-beta (Abeta) complex are reduced and oligomeric Abeta increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples.J. Biol. Chem. 2013; 288: 5914-5926Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Further pathology includes neuronal dysfunction, neuroinflammation, and cerebrovascular dysfunction (CerVD). Hence, it is essential to study the interactive role of AD risk factors: age, sex and APOE genotype in the development of human AD pathology using mouse models. In vivo progress to determine the effects of the human (h)-APOE genotypes on AD pathology has been limited by the lack of a tractable familial AD-Tg (FAD-Tg) mouse model expressing h-APOE rather than mouse (m)-APOE [for complete review on the introduction of h-APOE into FAD-Tg mouse models see (21.Tai L.M. Youmans K.L. Jungbauer L. Yu C. Ladu M.J. Introducing human APOE into Abeta transgenic mouse models.Int. J. Alzheimers Dis. 2011; 2011: 810981PubMed Google Scholar)]. Why is this a critical issue? The m-apoE is structurally and functionally distinct from h-apoE. While the three human isoforms of apoE differ by a single amino acid change at residues 112 and 158 (apoE2Cys,Cys, apoE3Cys,Arg, apoE4Arg,Arg), m-apoE is expressed as a single isoform and differs from h-apoE by ∼100–300 amino acids. The disparity between m- and h-apoE is relevant for virtually all AD-relevant pathology, including Aβ deposition and clearance, neuroinflammation, tau pathology, neural plasticity, and CerVD (22.Trommer B.L. Shah C. Yun S.H. Gamkrelidze G. Pasternak E.S. Ye G.L. Sotak M. Sullivan P.M. Pasternak J.F. LaDu M.J. ApoE isoform affects LTP in human targeted replacement mice.Neuroreport. 2004; 15: 2655-2658Crossref PubMed Scopus (96) Google Scholar, 23.Trommer B.L. Shah C. Yun S.H. Gamkrelidze G. Pasternak E.S. Stine W.B. Manelli A. Sullivan P. Pasternak J.F. LaDu M.J. ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-beta1–42.Neurobiol. Dis. 2005; 18: 75-82Crossref PubMed Scopus (0) Google Scholar, 24.Bien-Ly N. Andrews-Zwilling Y. Xu Q. Bernardo A. Wang C. Huang Y. C-terminal-truncated apolipoprotein apoE4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice.Proc. Natl. Acad. Sci. 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Holtzman D.M. 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. 2005; 25: 2803-2810Crossref PubMed Scopus (221) Google Scholar, 29.Oddo S. Caccamo A. Cheng D. LaFerla F.M. Genetically altering Abeta distribution from the brain to the vasculature ameliorates tau pathology.Brain Pathol. 2009; 19: 421-430Crossref PubMed Scopus (0) Google Scholar). Further, many APOE/FAD-Tg models express h-apoE under heterologous promoters that may be activated by stressors [glial fibrillary acidic protein (GFAP) (27.Fagan A.M. Watson M. Parsadanian M. Bales K.R. Paul S.M. Holtzman D.M. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease.Neurobiol. Dis. 2002; 9: 305-318Crossref PubMed Scopus (207) Google Scholar, 30.Holtzman D.M. Bales K.R. Tenkova T. Fagan A.M. Parsadanian M. Sartorius L.J. Mackey B. Olney J. McKeel D. Wozniak D. et al.Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2000; 97: 2892-2897Crossref PubMed Scopus (691) Google Scholar)], or by cell types that are not the primary producers of apoE [neuron-specific enolase (31.Buttini M. Yu G.Q. Shockley K. Huang Y. Jones B. Masliah E. Mallory M. Yeo T. Longo F.M. Mucke L. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation.J. Neurosci. 2002; 22: 10539-10548Crossref PubMed Google Scholar)], rather than the endogenous m-apoE promoter. Currently, the best option is the APOE-knock-in or targeted-replacement (TR) mice, developed to replace the coding domain for m-APOE with the coding domain of each of the h-APOE genotypes (32.Sullivan P.M. Mezdour H. Aratani Y. Knouff C. Najib J. Reddick R.L. Quarfordt S.H. Maeda N. 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: 17972-17980Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar). In APOE-TR mice, glial cells express h-APOE in a native conformation at physiologically regulated levels, and in the same temporal and spatial pattern as endogenous m-APOE. Thus, it is critical to conduct mechanistic and preclinical therapeutic studies in mice that incorporate h-APOE in a relevant context. Operationally, relative to m-APOE, the h-APOE genotypes delay AD pathology in FAD-Tg mouse models, as illustrated in Table 1. This table is designed to be a representation, using a composite of several FAD-Tg mouse models (27.Fagan A.M. Watson M. Parsadanian M. Bales K.R. Paul S.M. Holtzman D.M. 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Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy.Stroke. 2015; 46: 1633-1640Crossref PubMed Scopus (20) Google Scholar, 46.Irizarry M.C. Rebeck G.W. Cheung B. Bales K. Paul S.M. Holzman D. Hyman B.T. Modulation of A beta deposition in APP transgenic mice by an apolipoprotein E null background.Ann. N. Y. Acad. Sci. 2000; 920: 171-178Crossref PubMed Google Scholar) and Aβ pathology as an example of AD phenotype. First, Aβ pathology is significantly delayed when FAD-Tg mice are crossed with APOE-KO mice, eliminating m-APOE (Table 1: compare A to B) (27.Fagan A.M. Watson M. Parsadanian M. Bales K.R. Paul S.M. Holtzman D.M. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease.Neurobiol. Dis. 2002; 9: 305-318Crossref PubMed Scopus (207) Google Scholar, 30.Holtzman D.M. Bales K.R. Tenkova T. Fagan A.M. Parsadanian M. Sartorius L.J. Mackey B. Olney J. McKeel D. Wozniak D. et al.Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2000; 97: 2892-2897Crossref PubMed Scopus (691) Google Scholar, 39.Bales K.R. Verina T. Cummins D.J. Du Y. Dodel R.C. Saura J. Fishman C.E. DeLong C.A. Piccardo P. Petegnief V. et al.Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 1999; 96: 15233-15238Crossref PubMed Scopus (403) Google Scholar, 40.Dodart J.C. Mathis C. Bales K.R. Paul S.M. Ungerer A. Behavioral deficits in APP(V717F) transgenic mice deficient for the apolipoprotein E gene.Neuroreport. 2000; 11: 603-607Crossref PubMed Google Scholar, 46.Irizarry M.C. Rebeck G.W. Cheung B. Bales K. Paul S.M. Holzman D. Hyman B.T. Modulation of A beta deposition in APP transgenic mice by an apolipoprotein E null background.Ann. N. Y. Acad. Sci. 2000; 920: 171-178Crossref PubMed Google Scholar). Second, Aβ pathology is further delayed when h-APOE-Tg mice are crossed with FAD-Tg/APOE-KO mice (Table 1: compare B to C) (28.Fryer J.D. Simmons K. Parsadanian M. Bales K.R. Paul S.M. Sullivan P.M. Holtzman D.M. 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. 2005; 25: 2803-2810Crossref PubMed Scopus (221) Google Scholar, 30.Holtzman D.M. Bales K.R. Tenkova T. Fagan A.M. Parsadanian M. Sartorius L.J. Mackey B. Olney J. McKeel D. Wozniak D. et al.Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2000; 97: 2892-2897Crossref PubMed Scopus (691) Google Scholar, 47.Bales K.R. Liu F. Wu S. Lin S. Koger D. DeLong C. Hansen J.C. Sullivan P.M. Paul S.M. Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice.J. Neurosci. 2009; 29: 6771-6779Crossref PubMed Scopus (189) Google Scholar, 48.Castellano J.M. Kim J. Stewart F.R. Jiang H. DeMattos R.B. Patterson B.W. Fagan A.M. Morris J.C. Mawuenyega K.G. Cruchaga C. et al.Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance.Sci. Transl. Med. 2011; 3: 89ra57Crossref PubMed Scopus (713) Google Scholar). Thus, incorporation of h-APOE into FAD-Tg mice that normally begin to develop pathology at 8–10 months delays the development of pathology to 12–16 months (27.Fagan A.M. Watson M. Parsadanian M. Bales K.R. Paul S.M. Holtzman D.M. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease.Neurobiol. Dis. 2002; 9: 305-318Crossref PubMed Scopus (207) Google Scholar, 28.Fryer J.D. Simmons K. Parsadanian M. Bales K.R. Paul S.M. Sullivan P.M. Holtzman D.M. 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