APOE2 is associated with longevity independent of Alzheimer's disease
- National Center for Geriatrics and Gerontology, Japan
- Mayo Clinic, United States
- University of Texas Health Science Center at San Antonio, United States
- Durham Veterans Health Administration Medical Center's Geriatric Research, United States
- Georgetown University Medical Center, United States
Abstract
Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical database as well as animal models. Notably, APOE2 was associated with preserved physical activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of apoE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.
Data availability
All source data files of animal experiments (Figure 2, Figure 4, Supplementary File 1d, and Supplementary File 1f) are included in the manuscript and supporting files. The clinical data are available from NACC (https://www.alz.washington.edu/WEB/researcher_home.html) upon request: distributing any data to a third party, who is not a collaborator or co-authors, is strictly prohibited by NACC.
Article and author information
Author details
Funding
National Institute on Aging (RF1AG057181)
- Guojun Bu
Naito Foundation
- Mitsuru Shinohara
BrightFocus Foundation
- Mitsuru Shinohara
National Center for Geriatrics and Gerontology
- Mitsuru Shinohara
Hori Sciences and Arts Foundation
- Mitsuru Shinohara
National Institute on Aging (R37AG027924)
- Guojun Bu
National Institute on Aging (R01AG046205)
- Guojun Bu
National Institute on Aging (RF1AG051504)
- Guojun Bu
National Institute on Aging (P01NS074969)
- Guojun Bu
National Institute on Aging (P30AG062677)
- Guojun Bu
Cure Alzheimer's Fund
- Guojun Bu
National Institute on Aging (R21AG052423)
- Takahisa Kanekiyo
Japan Heart Foundation
- Mitsuru Shinohara
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All cohorts examined in this study were generated from homozygous breeding pairs, group housed without enrichment structures in a specific pathogen-free environment in ventilated cages and used in experiments according to the standards established by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC, Protocol# A58312).
Copyright
© 2020, Shinohara et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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APOE2 is associated with longevity independent of Alzheimer's disease
eLife 9:e62199.
https://doi.org/10.7554/eLife.62199
Further reading
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Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3ar1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.
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Background:
Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined.
Methods:
We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints.
Results:
We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression.
Conclusions:
JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS.
Funding:
NIAMS, Global Down Syndrome Foundation.
Clinical trial number:
