More clinically relevant mouse models for neurodegenerative diseases are sorely needed as tools to study disease progression and to develop future therapeutics. At last month's virtual International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), two separate research groups labs offered some new options.
- New mouse models replace the mouse tau gene with the human one.
- Others combine ApoE4, TREM2 R47H, humanized Aβ42, and diet to model LOAD.
- Both approaches more closely mimic human tauopathies and AD.
Michael Koob, University of Minnesota, Minneapolis, presented data on targeted replacement mice in which he swapped out the mouse MAPT tau gene against the human MAPT gene. His group also produced five strains into which they incorporated a pathogenic variant of the human MAPT gene, enabling scientists to mimic the genetics of different human tauopathies. Adrian Oblak and colleagues at Indiana University, Indianapolis, and at Jackson Laboratory (JAX), Bar Harbor, Maine, used a multi-gene approach to generate mouse models of late-onset AD, aka LOAD, which afflicts people 65 or older. The mice were fed a high-fat Western diet to examine the impact of some environmental influences on disease progression.
Targeted Replacement of MAPT
In 1998, several research groups first discovered pathogenetic variants in the MAPT gene on chromosome 17 as the underlying cause of certain tauopathies (Hutton et al., 1998; Dumanchin et al., 1998; Spillantini et al., 1998; Clark et al., 1998). Twenty-three years later, dozens more pathogenic tau mutations have been reported; however, exactly how any of them leads to dementia remains unknown.
Mouse models incorporating some of these mutations (see Alzforum Research Models database) have focused primarily on disease phenotypes, above all the signature protein deposits, not on the molecular genetic modifications that lead to these traits. “When you model toward the phenotype, you miss a lot of the subtleties,” Koob told Alzforum. In humans, disease phenotypes take 40 to 60 years to develop. “If you model having dementia when the mouse is 4 months old, you probably did something very different than what happens in a human, because that’s just not how that works,” Koob said
To address this problem, the NIH in 2019 funded the AD-related dementias gene replacement project, of which Koob is the PI. It aims to evaluate the impact of MAPT mutations within the context of the genomic sequence. Koob and colleagues developed a gene-replacement technology that allows them to take out the mouse MAPT gene and substitute in the entire human MAPT gene.
They produced two different wild-type versions of the mice. In H1.0, all 190,000 base pairs of the human sequence are of the H1 haplotype; in H2.1, the first 23,000 base pairs are H1, and the next 167,000 base pairs are of the H2 haplotype. The H1 haplotype block is more common, and carries more risk of neurodegeneration than the H2 haplotype (e.g., Mar 2019 news; Sep 2005 news). To induce a disease phenotype in these wild-type mice, the scientists inflicted a mild traumatic brain injury. After one week, they saw an accumulation of phosphorylated tau near the TBI site.
In addition, the scientists generated five pathogenic variant lines with single nucleotide changes in exon 9, exon 10, and intron 10. In people, these mutations lead to diseases including frontotemporal dementia and Pick’s disease.
Previously, researchers at the University of North Carolina, Chapel Hill, had developed a mouse model with targeted replacement of the endogenous murine ApoE gene with each of the human ApoE alleles. These mice have proven useful, for example in studying an anti-ApoE antibody that removes plaques from both the mouse brain's parenchyma and blood vessels without causing ARIA (Feb 2021 news). The mouse model out of Koob’s lab is the first to replace MAPT in a similar way.
Koob plans to make these mice available without restrictions to the research community as soon as possible. For this, Koob’s lab partners with JAX, which already has the H2.1 model available.
“The mouse models expressing human tau developed in the Koob lab will be a great resource for the AD and ADRD research effort,” Mike Sasner wrote to Alzforum. Sasner directs the Model Organism Development & Evaluation for Late-Onset AD, aka MODEL-AD, program. “While transgenic tau models—particularly Peter Davies’ ‘hTAU’ model—have been widely used for many years, the genome replacement mice should be much better models to study the underlying pathophysiology of AD and FTDs and are more translationally relevant for preclinical studies,” Sasner wrote.
Modeling Late-Onset Alzheimer's
Another limitation of current mouse models is that many reflect autosomal-dominant, familial AD, which accounts for fewer than 1 percent of people with Alzheimer's. Many of the older models overexpress their transgenes, causing artifactual phenotypes. To address these problems, the NIH started the MODEL-AD consortium (Oct 2019 news; Oblak et al., 2020).
As part of the MODEL-AD project, Oblak at IU and her team developed several LOAD knock-in mouse strains. Their LOAD1 mice have human ApoE4 and the TREM2 R47H variant knocked in; the LOAD2 mouse expresses knocked-in human ApoE4, TREM2 R47H, and humanized Aβ42.
Using these mice, Oblak and colleagues can ask such questions as how AD progression is influenced by environmental and lifestyle factors such as diet. A high-fat Western diet has been shown to boost TREM2 in microglia (Mar 2016 news). The scientists fed the LOAD1 and 2 mice a 45 percent high-fat and sugary chow from 2 to 12 months of age, collecting fecal and blood samples along the way. At AD/PD, Oblak showed that by 12 months of age, blood glucose and cholesterol levels were up in both mouse strains. The LOAD2 mice also had higher blood concentrations of the proinflammatory cytokines TNFα and IL10, and of neurofilament light chain, than did LOAD1 mice.
Combining risk variants for LOAD AD with environmental exposures such as a high-fat diet can produce a more relevant model for preclinical testing, Oblak said during the conference's live discussion. She believes that just because these models don’t have an overt neuropathological phenotype doesn’t mean they aren’t representative of the human condition.
“These predementia steps can be modeled really well in mice,” said Koob. “But this hasn’t been appreciated, because reviewers are focused on dramatic changes.” He hopes more groups will use the LOAD model.
With ever more models to choose from (peruse at Alzforum Research Models database), the question on many scientists’ minds is: Which one is the best? “There is never going to be one perfect model,” Frank LaFerla, University of California, Irvine, said during the live discussion. “What specific questions you are seeking to address determines which model you would pick.” LaFerla is a member of the MODEL-AD consortium.—Helen Santoro
- Unequal: Some Tau Haplotypes Carry More Risk Than Others
- Tau Shows Subtle Hints of Genetic Association
- Would ApoE Make a Better Therapeutic Target Than Aβ?
- NIH Funds Translational Research Centers to Accelerate AD Drug Discovery
- Microglial Marker TREM2 Rises in Early Alzheimer’s and on Western Diet
Research Models Citations
- Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
- Dumanchin C, Camuzat A, Campion D, Verpillat P, Hannequin D, Dubois B, Saugier-Veber P, Martin C, Penet C, Charbonnier F, Agid Y, Frebourg T, Brice A. Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum Mol Genet. 1998 Oct;7(11):1825-9. PubMed.
- Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC. Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. 1998 Nov;153(5):1359-63. PubMed.
- Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, Andreadis A, D'Souza I, Lee VM, Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13103-7. PubMed.
- Oblak AL, Forner S, Territo PR, Sasner M, Carter GW, Howell GR, Sukoff-Rizzo SJ, Logsdon BA, Mangravite LM, Mortazavi A, Baglietto-Vargas D, Green KN, MacGregor GR, Wood MA, Tenner AJ, LaFerla FM, Lamb BT, and The MODEL‐AD, Consortium. Model organism development and evaluation for late-onset Alzheimer's disease: MODEL-AD. Alzheimers Dement (N Y). 2020;6(1):e12110. Epub 2020 Nov 23 PubMed.
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