Cornucopia: LOADs of New Mouse Models Available

Alzheimer’s researchers have long wished for better mouse models. That is now coming true. Scientists at the Jackson Laboratory in Bar Harbor, Maine, are cranking out numerous lines that express humanized Aβ and tau in combination with late-onset AD gene variants in APOE, TREM2, or genome-wide association hits.

  • MODEL-AD consortium has produced polygenic LOAD models.
  • Separate efforts are creating protective and inducible APOE variant models.
  • Glial reporter strains may help decipher the biology of these cells.

In contrast to the overexpression models that have been used for decades, the new mice tend to have subtle phenotypes, which show up only after age, or other risk factors such as a high-fat diet, have exacted a toll. Scientists hope these mice will more accurately reflect the changes that occur in people with AD, Michael Sasner at the Jackson Laboratory (JAX) told Alzforum.

“The disease models we have been using to date have not been translational,” Sasner noted, meaning that treatment benefits in them failed to predict success in subsequent human trials. He believes the new ones will do a better job, because transcriptional studies show they capture many of the biological changes in AD brain that traditional models miss.

Sasner sat down with Alzforum to go over what models are available now, which ones are coming, and how they could be used. The new mouse lines are the product of two different initiatives: NIA’s Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium, and a separate project to produce mouse models requested by the AD community. The latter fall into two categories: disease models and reporter strains for basic research.

Another difference from some earlier mouse lines? All of the new ones are freely available to the research community, and data from them are shared via the National Institute on Aging’s AD Knowledge Portal. Efforts to characterize the new lines are ongoing, and JAX invites the research community to try them out and add their findings to the knowledge base.

Digging Into GWAS Hits
MODEL-AD is the longer-running project of the two. It brings together researchers at Indiana University, the University of Pittsburgh, the University of California at Irvine, Jackson Laboratory, and the biomedical research nonprofit Sage Bionetworks in Seattle. Established in 2017, the consortium’s goal is to speed up the development of AD therapeutics by providing more representative models for drug testing (Jan 2017 news). NIA has renewed the initial five-year grant for another five years, until 2027.

The MODEL-AD pipeline starts with knocking in human AD risk genes, then characterizing the resulting mice with a slew of “omics” analyses and comparing the results to human data. The researchers look for changes in mRNA, proteins, and metabolites that resemble those seen in LOAD brain. The most promising models undergo deeper phenotyping via multiple modalities, including neuropathology, fluid biomarkers, and neuroimaging, with a focus on measures that translate well to human studies.

For example, for cognitive testing, the scientists use not the water maze but electroencephalography and touchscreen tests. Similar to human tests of attention, the mice are rewarded for touching a bright spot on the screen with their nose (Mar 2011 news).

Mice with AD-like changes such as plaques, phosphorylated tau, neuroinflammation, dendritic spine loss, or attention deficits go on to preclinical testing, where researchers determine whether drugs that have been studied in people, such as levetiracetam, verubecestat, and aducanumab, have similar effects in mice as they do in people. This serves to establish a sense of their predictive validity.

The first lines in this project used key AD genes: APP, tau, APOE, and TREM2. Because the well-known pathological APP and tau mutations are absent in late-onset AD, the researchers knocked in wild-type humanized sequences. Rather than humanize the entire APP gene, they edited only the Aβ42 sequence. Human Aβ42 varies by three amino acids from the mouse peptide, and it is more neurotoxic. For tau, the researchers humanized the entire gene so that it would be processed the way it is in human brain. Human tau forms six isoforms, compared to three in mice. The scientists hope that humanizing the gene will bring the ratio of 3R to 4R isoforms closer to what it is in human brain. In separate mouse lines, researchers knocked in each of the common APOE alleles. Although other groups had previously created APOE knock-ins, those were not widely or freely available, Sasner noted. For TREM2, they inserted the LOAD variants R47H and Y38C, or deleted the gene. See below for a list of available models to date.

These basic lines in hand, the scientists then crossed them to build polygenic models. One, dubbed LOAD2, combines humanized Aβ42 with APOE4 and R47H TREM2 (Apr 2021 conference news). Another, LOAD3, combines humanized Aβ42 and humanized wild-type tau with APOE4.

LOAD2 and LOAD3 themselves constitute backgrounds into which geneticists can drop additional variants. Some of the first such polygenic lines express pathogenic variants of the lipid transporter ABCA7, the metabolic gene MTHFR, or the immune gene PLCG2. PLCG2 has a well-known protective variant, but MODEL AD researchers instead tested the risk variant M28L.

They are also generating mice that express coding variants of numerous other GWAS genes, as well as some pathogenic non-coding variants.

  Name Description
hAPP and hTAU    
  hAbeta KI Humanized Abeta42
  hAbeta-loxP-KI Humanized Abeta42, floxed
  MAPT(H1.0)-GR Humanized tau, haplotype 1
  MAPT(H2.1)-GR Humanized tau, haplotype 2
     
TREM2 variants    
  Trem2 KO TREM2 knockout
  Trem2 fKO TREM2 knockout, floxed
  Trem2R47H<HSS> TREM2 R47H variant
  Trem2Y38C TREM2 Y38C variant
  hTREM2*R47H Humanized TREM2 R47H variant
     
APOE variants    
  hAPOE2 APOE2 variant
  hAPOE3 APOE3 variant
  hAPOE4 APOE4 variant
  **hAPOE3-Christchurch Christchurch variant in APOE3
  **hAPOE4-Christchurch Christchurch variant in APOE4
  **hAPOE3-Jacksonville Jacksonville variant in APOE3
  **hAPOE4>hAPOE3 Inducible APOE4 to APOE3
  **hAPOE3>hAPOE4 Inducible APOE3 to APOE4
  **hAPOE3>hAPOE2 Inducible APOE3 to APOE2
     
APP mutants    
  APPSAA Swedish, Arctic, Austrian APP mutations
  **APPSDI Swedish, Dutch, Iowa APP mutations
  **APPSFL Swedish, Florida, London APP mutations
     
Tau mutants    
  hMAPT(H1.0*N279K)-GR N279K variant on haplotype 1
  hMAPT(H1.0*P301L)-GR P301L variant on haplotype 1
  hMAPT 10IVS+16 C>T 10IVS+16 C>T variant on haplotype 1
     
Base models    
  LOAD1 B6.APOE4/TREM2R47H
  LOAD2 B6.APOE4/ TREM2R47H/hAbeta
  **LOAD3 B6.APOE4/hAbeta/hTAU
     
Crosses    
  LOAD2.ABCA7.A1527G ABCA7 A1527G variant on LOAD2 background
  LOAD2.MTHFR.C677T MTHFR C677T variant on LOAD2 background
  LOAD2.PLCG2.M28L PLCG2 M28L variant on LOAD2 background
  **APPSAA/hTAUN279K/APOE4 APPSAA with TAUN279K and APOE4
     
**Reporter lines    
  APOE cre-dependent reporter  
  Spp1-TdTomato reporter  
  Sall1-GFP reporter  
  Grn-mOrange2 reporter  
  MS4A7-TdTomato reporter  
  Lcn2-TdTomato reporter  
     
  ** These mice are still in development.  

 

How well do these polygenic mouse lines represent AD pathology? The mice start out healthy, and gene expression in their brains bears little resemblance to patterns seen in AD brain as per postmortem bulk transcriptomic data from AMP-AD (Wan et al., 2020). However, by 1 year of age, gene expression in specific brain regions exhibits AD-like profiles (Preuss et al., 2020). 

The exact pattern depends on what LOAD gene a given model carries. For example, ABCA7 polygenic mice alter cell-cycle and protein-folding gene expression, mimicking changes seen in AD brain. MTHFR mice suppress fatty acid metabolism, and PLCG2 mice, synaptic vesicle genes (Reagan et al., 2022). These nuanced changes stand in contrast to those in traditional transgenic overexpression models such as 5XFAD, which mostly ramp up inflammatory genes. “We think 5XFAD only mimics the immune response to amyloid, whereas these models are hitting other pathways,” Sasner said.

Unlike 5XFAD mice, which deposit amyloid starting at 2 months of age, the newer models start developing problems much later in life. JAX rears the mice to 24 months to fully assess their subtle phenotypes.

That said, layering on environmental risk factors amplifies things. For example, a high-fat diet jacked up proinflammatory cytokines in year-old PLCG2-M28L mice (Oblak et al., 2022). In LOAD2 mice, a high-fat diet boosted insoluble Aβ42, neuroinflammation, and plasma NfL by one year, and cortical neuronal loss in females by 18 months, but caused no plaque deposition or memory problems. The scientists are considering adding other insults, such as heavy metals and ozone to model the effects of pollution (Mar 2004 news; Feb 2012 news; May 2020 news).

“We don’t see a lot [of pathology] in some of these base models on a normal chow diet. We think adding environmental factors will be useful,” Sasner said. This may better mimic the etiology of late-onset AD, which stems from a confluence of genetic and environmental risk factors.

Researchers throughout the field have been slow to shift toward using MODEL-AD mice, Sasner told Alzforum. A first publication is in the works and may generate interest. JAX is providing mice to several research groups at pharma companies, which are eager to move away from using transgenic models and toward knock-ins.

Knock-in Familial and Protective Mutations
For those who want more dramatic AD phenotypes than the LOAD models afford, fear not. In a separate initiative, JAX collaborates with academic labs to create FAD and other knock-ins. One project inserts multiple pathogenic APP SNPs into the mouse genome against a background of humanized Aβ42. For example, the SAA model, which was made in collaboration with Denali Therapeutics, combines the Swedish, Arctic, and Austrian mutations. The mice develop parenchymal amyloid in the cortex and hippocampus starting at 4 months old (Xia et al., 2022). 

The SDI model mixes Swedish, Dutch, and Iowa mutations. It has mostly cerebral amyloid angiopathy, which develops by 18 months in heterozygous mice; homozygous mice are being characterized now. “We think these are two relatively pure models that will be useful for studying how amyloid kicks off AD progression,” Sasner noted. A third APP model, with Swedish, Florida, and London mutations (SFL), boosts production of wild-type Aβ42.

The field already has some APP knock-in options with the APPNL-F and APPNL-G-F models. They feature a different mix of mutations and were not widely available, though the RIKEN Center for Brain Science in Wako, Japan, which supplies the mice, recently loosened restrictions (Sep 2022 news). 

For aficionados of APOE, JAX researchers have generated specialized mice, including ones that carry the protective Christchurch and Jacksonville mutations on an APOE3 or E4 background (Nov 2019 news; Oct 2021 news; Sep 2022 news).

They also made three inducible APOE mice that, when activated, will replace exon 4 of the gene with one of two other alleles, allowing researchers to switch APOE4 to APOE3 in one mouse, APOE3 to E4 in another, or switch APOE3 to the protective E2 variant in the third. These inducible genes can be activated in specific cell types, for example only in astrocytes, microglia, or neurons. “This gets at the cell-type specificity associated with the risk alleles, opening up a lot of research possibilities,” Sasner noted.

In collaboration with Michael Koob at the University of Minnesota, Minneapolis, JAX scientists are making pathogenic tau variants on a human tau background. So far, these include frontotemporal dementia variants N279K and P301L. These are not AD genes, but good mouse models of AD will require tau pathology, and Sasner and colleagues plan to cross these with other models. One such cross combines SAA mice with N279K tau and APOE4 in an attempt to generate amyloid, tau, and vascular pathology in one animal. These mice, like many of the lines, have not been fully characterized yet.

Studying Biology Via Reporter Strains
The goal behind many mouse models is to test therapeutics, but that is not their only purpose. Equally important is having strains that allow scientists to dissect the biology of the disease, particularly the role of glial cells in amyloidosis. Despite intensive research on these cells, scientists have no consensus on what factors make microglia and astrocyte responses helpful or harmful, and how that varies by disease stage. Reporter models will help track the timing, extent, and type of glial activation. They could also help reveal the effects of therapeutic interventions on the glial response. JAX is generating numerous such reporter models (see table above).

In collaboration with Beth Stevens at Boston Children’s Hospital, and Soyon Hong at University College London, JAX generated several reporter strains that link a fluorescent tag to a microglial gene such as Spp1 or MS4A7, allowing researchers to see where and when the gene is expressed (see De Schepper et al., 2022, preprint). Spp1 is part of the disease-associated microglia signature in mice, and MS4A7 harbors AD risk variants. JAX is also making astrocyte-specific reporters in collaboration with Shane Liddelow at New York University. In addition, JAX has generated a fluorescent-tagged APOE reporter that can be activated in specific cell types such as astrocytes or neurons. Most APOE is made by astrocytes, but other cells also produce it, and studies often have trouble determining what cell type contributes most to a given APOE effect.

These reporter strains can be crossed with amyloidosis and tau models to glean clues to the role of glia cells in the disease. For example, crossing the Spp1 reporter with SAA mice would help pin down the role of this DAM gene in disease. “Understanding the basic biology of microglia and astrocytes in the context of amyloid and tau is the next step for understanding the disease so we can do a better job of treating it,” Sasner said.—Madolyn Bowman Rogers

Comments

  1. There is no doubt that we need more murine models for AD research, but much of the work with existing models is being misinterpreted. The vast majority of studies in mouse models of amyloidosis or tauopathy treat mice with test agents very early in a prevention type of paradigm. Most studies in humans have treated long after the pathology has matured, in a therapeutic paradigm. These are apples and oranges.

    One of the few treatments successful in APP mice in a therapeutic paradigm, immunotherapy, works even when started long after amyloid has matured to remove pathology and rescue memory loss (Wilcock et al., 2004; DeMattos et al., 2012). The mouse models also predicted ARIA, via micro-hemorrhages and increased angiopathy (Pfeifer et al., 2002; Wilcock et al., 2004). Thus far, immunotherapy is the only treatment that can remove amyloid and slow cognitive decline when applied in a therapeutic paradigm in humans (aducanumab, donanemab, lecanemab). It is likely that as more of the "failed" approaches in AD therapeutic paradigms are tested in prevention paradigms, some will also have benefit preventing AD, as they did in APP mice. 

    A final comment: Any mouse that does not have amyloid plaques or tau tangles is not a model for AD, as these pathologies define the disease. Perhaps the models without amyloid represent individuals carrying risk genes who do not get disease, but by definition, they are not AD models.

    I am awed by the sophistication of the scientists making these models and the insights they will bring as we develop more agents for AD. That said, we need not denigrate the successes of the existing models to justify the development and study of new and, possibly, improved ones. Anti-amyloid immunotherapy was the first intervention to show success in APP mice. It is the first intervention to slow decline in people living with AD. It just took two decades to get here.

    References:

    Demattos RB, Lu J, Tang Y, Racke MM, DeLong CA, Tzaferis JA, Hole JT, Forster BM, McDonnell PC, Liu F, Kinley RD, Jordan WH, Hutton ML. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice. Neuron. 2012 Dec 6;76(5):908-20. PubMed.

    Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. PubMed.

    Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004 Dec 8;1(1):24. PubMed.

    View all comments by Dave Morgan

  2. There seems to be some misunderstanding about our App (Saito et al., 2014; Watamura et al., 2022), MAPT (Hashimoto et al., 2019), and Psen1 (Sasaguri et al., 2018) knock-in mice, some of which are even unreferred-to. These mice have been freely provided to all the basic researchers worldwide. As a result, the number of mouse users exceeded 600 a long time ago: the only continents where the mice do not exist are Africa and Antarctica. Consistently, our original paper is one of the most highly cited according to Clarivate Analytics. We chose to deposit our mice to RIKEN BioResource Center rather than to the Jackson Laboratory.

    I have some comments that may help the students and postdocs who may be using the LOAD models. As Dr. Morgan indicated, SNPs in most GWAS-identified genes are unlikely to exert substantial effects, except for ApoE and TREM2, because each of their odds ratios is very small. There are more than 70 risk-associated genes thus far identified (Bellenguez et al., 2022), so it would be very interesting to analyze the mice that carry most, if not all, of these SNPs, although the number of mouse lines to create would be astronomic. Here is a tip for humanized tau mouse user. We have generated a number of mutant MAPT knock-in mice. One thing for sure is that the knock-in mice carrying the P301S mutation showed no tau pathology up to 24 months.

    References:

    Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.

    Watamura N, Sato K, Shiihashi G, Iwasaki A, Kamano N, Takahashi M, Sekiguchi M, Mihira N, Fujioka R, Nagata K, Hashimoto S, Saito T, Ohshima T, Saido TC, Sasaguri H. An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities. Sci Adv. 2022 Jun 10;8(23):eabm6155. Epub 2022 Jun 8 PubMed.

    Hashimoto S, Matsuba Y, Kamano N, Mihira N, Sahara N, Takano J, Muramatsu SI, Saido TC, Saito T. Tau binding protein CAPON induces tau aggregation and neurodegeneration. Nat Commun. 2019 Jun 3;10(1):2394. PubMed.

    Sasaguri H, Nagata K, Sekiguchi M, Fujioka R, Matsuba Y, Hashimoto S, Sato K, Kurup D, Yokota T, Saido TC. Introduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID. Nat Commun. 2018 Jul 24;9(1):2892. PubMed.

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    View all comments by Takaomi Saido

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References

News Citations

  1. Building Better Mouse Models for Late-Onset Alzheimer’s
  2. Research Brief: Attention Tests With a Touch of Class—or Maybe Genus
  3. New Mouse Models Better Mimic Tauopathy, Alzheimer's
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  2. MAPT(H2.1)-GR
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  4. Trem2 flox
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External Citations

  1. MODEL-AD
  2. AD Knowledge Portal
  3. hAbeta KI
  4. hAbeta-loxP-KI
  5. Trem2R47H
  6. Trem2Y38C
  7. hTREM2*R47H
  8. APPSAA
  9. hMAPT(H1.0*N279K)-GR
  10. hMAPT(H1.0*P301L)-GR
  11. hMAPT 10IVS+16 C>T
  12. LOAD2.ABCA7.A1527G
  13. LOAD2.MTHFR.C677T
  14. LOAD2.PLCG2.M28L

Further Reading

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