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Cited by 66Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H

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Kotredes, Kevin P., Oblak, Adrian, Pandey, Ravi S., Lin, Peter Bor-Chian, Garceau, Dylan, Williams, Harriet, Uyar, Asli, O’Rourke, Rita +14 more·2021·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2021.735524PMC PMC8544520
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Abstract

Late-onset Alzheimer’s disease (AD; LOAD) is the most common human neurodegenerative disease, however, the availability and efficacy of disease-modifying interventions is severely lacking. Despite exceptional efforts to understand disease progression via legacy amyloidogenic transgene mouse models, focus on disease translation with innovative mouse strains that better model the complexity of human AD is required to accelerate the development of future treatment modalities. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes parallel to those often muted by the early and aggressive aggregate formation in popular mouse strains. In addition to extracellular deposits of amyloid plaques and inclusions of the microtubule-associated protein tau, AD is also defined by synaptic/neuronal loss, vascular deficits, and neuroinflammation. These underlying processes need to be better defined, how the disease progresses with age, and compared to human-relevant outcomes. To create more translatable mouse models, MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) groups are identifying and integrating disease-relevant, humanized gene sequences from public databases beginning with APOEε4 and Trem2*R4 7H, two of the most powerful risk factors present in human LOAD populations. Mice expressing endogenous, humanized APOEε4 and Trem2*R4 7H gene sequences were extensively aged and assayed using a multi-disciplined phenotyping approach associated with and relative to human AD pathology. Robust analytical pipelines measured behavioral, transcriptomic, metabolic, and neuropathological phenotypes in cross-sectional cohorts for progression of disease hallmarks at all life stages. In vivo PET/MRI neuroimaging revealed regional alterations in glycolytic metabolism and vascular perfusion. Transcriptional profiling by RNA-Seq of brain hemispheres identified sex and age as the main sources of variation between genotypes including age-specific enrichment of AD-related processes. Similarly, age was the strongest determinant of behavioral change. In the absence of mouse amyloid plaque formation, many of the hallmarks of AD were not observed in this strain. However, as a sensitized baseline model with many additional alleles and environmental modifications already appended, the dataset from this initial MODEL-AD strain serves an important role in establishing the individual effects and interaction between two strong genetic risk factors for LOAD in a mouse host.

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  • All strains were validated using brain RNA-seq to confirm no off-target effects and no alterations in target transcript isoforms or expression levels.

    “All strains were validated using brain RNA-seq to confirm no off-target effects and no alterations in target transcript isoforms/expression levels (Kotredes et al., 2021).”

    From Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice (2022) · cites this paper as Kotredes et al., 2021

    The paper reports brain RNA-seq in Materials and Methods (RNA-Sequencing Experimental Design), but it does not say that this confirmed an absence of off-target effects. More decisively, the Discussion reports that the Trem2*R47H mutation created a novel splice site and reduced Trem2 transcript levels by approximately 20%—the opposite of the claimed absence of changes in target isoforms or expression. Page numbers are not available in our copy. (LLM, conf=0.93)

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  • Although APOE4 and TREM2R47H are strong genetic risk factors for LOAD in humans, TREM2R47H may be reducing the effect of the APOE4 variant when present together.

    “However, data now suggest that although APOE4 and TREM2R47H are strong genetic risk factors for LOAD in humans, TREM2R47H may be reducing the effect of the APOE4 variant when present together (Kotredes et al., 2021).”

    From Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice (2022) · cites this paper as Kotredes et al., 2021

    The Discussion states the opposite direction of effect: APOEε4 suppresses effects associated with Trem2*R47H, including its transcriptional and inflammatory responses in the mouse models. The paper also reports emerging evidence that APOEε4 carriers may not have increased AD risk from Trem2*R47H; it does not say Trem2*R47H reduces the effect of APOEε4. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Neuronal cell loss was not observed in LOAD1 mice, even at 24 months of age.

    “Neuronal cell loss was also not observed in LOAD1 mice, even at 24 months of age (Kotredes et al., 2021).”

    From Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice (2022) · cites this paper as Kotredes et al., 2021

  • In LOAD1 mice and controls aged 24 months, age but not genotype was the major factor driving changes.

    “LOAD1 mice and controls were aged 24 months and data showed age but not genotype was the major factor-driving changes in LOAD1 mice (Kotredes et al., 2021).”

    From Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice (2022) · cites this paper as Kotredes et al., 2021

  • LOAD1 mice provided a sensitized background for assessing additional genetic and environmental risk factors.

    “Therefore, these mice provided a sensitized background for assessing additional genetic and environmental risk factors (Kotredes et al., 2021).”

    From Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice (2022) · cites this paper as Kotredes et al., 2021

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Cited by

Sorted by citations

Authors
Kotredes, K. P., Oblak, A., Pandey, R. S., Lin, P. B.-C., Garceau, D., Williams, H., Uyar, A., O’Rourke, R., O’Rourke, S., Ingraham, C., Bednarczyk, D., Belanger, M., Cope, Z., Foley, K. E., Logsdon, B. A., Mangravite, L. M., Sukoff Rizzo, S. J., Territo, P. R., Carter, G. W., Sasner, M., Lamb, B. T., & Howell, G. R.
Affiliations
  • Jackson Laboratory (US)
  • Indiana University Bloomington (US)
  • University of Pittsburgh (US)
  • Sage Bionetworks (US)
Corresponding author
  • Lamb, Bruce T.
  • Howell, Gareth R.
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2021-10-11
Volume
13
Pages
735524-735524
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2021.735524
PMC
PMC8544520
OpenAlex
W3207717438
Cited by
66
References
20
Citations by year
2026: 10 · 2025: 9 · 2024: 12 · 2023: 26 · 2022: 9
FWCI
7.38
Type
journal article
Language
en
Update notices
corrigendum (2022-02-07)
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
Funders
National Institute on Aging (U54 AG054345)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
late-onset Alzheimer's disease, genetic risk factors, neuroinflammation, glycolytic metabolism, vascular perfusion, brain transcriptomics, sex differences, amyloid plaques, disease-modifying interventions

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