• 随着全球化的深入,跨文化交流和国际合作变得日益重要。
  • 隐私保护和数据安全成为数字时代的重要议题。
  • 数字货币的兴起正在改变传统金融体系的运作方式。
  • 生物技术在医药领域的应用为治疗复杂疾病提供了新的可能性。
  • 在线教育平台的兴起为全球学习者提供了新的学习途径。
  • 全球健康危机促使各国加强公共卫生体系的建设和改革。
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  • 随着在线教育的兴起,教育公平问题再次成为社会讨论的热点。
  • 数字货币的合法性和监管问题成为金融监管机构的新挑战。
  • 电子竞技的兴起改变了传统体育和娱乐行业的格局。
  • 随着全球化的深入,跨文化交流和国际合作变得日益重要。
  • 网络安全的挑战促使全球加强数据保护和隐私法规。
  • 生物技术在医药领域的应用为治疗复杂疾病提供了新的可能性。
  • 全球范围内的疫苗接种运动正在加速,为控制疫情带来希望。
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  • 随着全球健康危机的持续,心理健康问题成为社会关注的焦点。
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  • 电子商务的快速发展对传统零售业造成了巨大冲击。
  • 隐私保护和数据安全成为数字时代的重要议题。
  • Targeting IGF1R signaling for brain aging and Alzheimer’s disease | Park | Aging Pathobiology and Therapeutics

    Open Access | Commentary
    This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

    Targeting IGF1R signaling for brain aging and Alzheimer’s disease


    Joo Young Parka, Martin Darvasb, Warren Ladigesa, *

    a Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
    b Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA 98195, USA.

    * Corresponding author: Warren Ladiges
    Mailing address: Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
    Email: wladiges@uw.edu

    Received: 20 December 2022 / Accepted: 22 December 2022 / Published: 29 December 2022

    DOI: 10.31491/APT.2022.12.103

    Abstract

    The role of IGF1R signaling in the brain and its relationship to aging and neurological dysfunction is controversial. Because it was shown that low IGF1R activity consistently improved myocardial bioenergetics and function in hearts from aging mice, but not hearts from young mice, it was of interest to investigate this relationship in brain aging. We used CRISPR technology to develop a mouse model with targeted replacement of mouse IGF1R with the equivalent of the human R407H (IGF1RR407H) variant enriched in centenarians with a reduction in IGF1R protein activity. Middle-aged mice show improved cognitive performance thus possibly modeling IGF1R signaling in the aging brain, similar to what was reported in the aging heart. Because Alzheimer’s disease (AD) is an age-related disease, specific IGF1RR407H pathways could be therapeutic targets in mice with AAV vector-based AD as well as for overall brain aging.

    Keywords

    IGF1R signaling, IGF1RR407H variant, brain aging, cognition, Alzheimer’s disease


    Signaling of insulin/insulin-like growth factor-1 (IGF1) through the IGF1-receptor (IGF1R) is central to processes that modulate aging and lifespan in model organisms [1-2], as well as mortality and morbidity in humans [3]. IGF1R signaling controls cellular growth and metabolism through a wide variety of downstream pathways. A recent study by Abdellatif et al. [4] showed that low IGF1R activity consistently improved myocardial bioenergetics and function in hearts from aging mice, but not hearts from young mice, in an autophagy-dependent manner. They concluded that the relationship between IGF1R signaling and cardiac health is not linear, but biphasic, since mice with low IGF1R signaling exhibited poor cardiac function early in life, while young mice with increased IGF1R signaling showed a superior cardiac function that progressively declined with increasing age. Moreover, analyses of serum IGF1 levels and various clinical diseases lend further support for such antagonistic pleiotropy [5]: protection of young individuals with high IGF1 levels and increased disease risk in older individuals with higher IGF1 levels.
    While much work on IGF1R has focused on peripheral organs, there is reason to assume the same mechanism occurs in the brain. It has been shown that increased IGF1R signaling was apparent in postmortem brains of Alzheimer’s disease (AD) patients [6], suggesting that a long-term increase in activity is associated with the progression of AD neuropathology. Genetic ablation of IGF1R in neurons of aging mice can protect against neuroinflammation and memory impairment induced by A beta oligomers [7]. However, the role of IGF1R signaling in the brain and its relationship to aging and neurological dysfunction is controversial. For example, Tazearslan et al. [8] reported that age-related astrocyte dysfunction caused by diminished IGF1R signaling may contribute to the pathogenesis of AD and other age-related cognitive impairments. A possible explanation for the opposite effects to be in play may be that different downstream pathways respond differently with increasing age. Evidence to support this possibility showed that Ashkenazi Jewish centenarians were found to be enriched with variants in the IGF1R gene [9]. Individuals carrying two specific variants, A37T and R407H, had a significant reduction in IGF1R protein and its phosphorylation levels.
    Based on these observations, we used CRISPR technology to develop a mouse model with a targeted replacement of mouse IGF1R with the equivalent of the human R407H (IGF1RR407H) variant [10]. The objective was to establish a precision animal model that could help provide definitive answers to the role of IGF1R signaling in aging, including age-associated conditions such as cardiac aging and neurodegeneration. Since IGF1RR407H disrupts phosphorylation levels of ERK and AKT but not IGF1R-IGF1 binding, these specific pathways (and probably others) can be interrogated using this newly developed mouse line. Thus, we can study how a single variant may down-regulate IGF1R signaling in a more precise pathway-specific manner to provide a protective environment to delay brain aging and prevent the development of neurological conditions such as Alzheimer’s disease (AD). Is this mouse line then a model of the biphasic signaling by IGF1R in the aging brain similar to what Abdellatif et al. [4] reported in the aging heart? Perhaps, but more work is needed. We have not observed any adverse phenotypic effects at younger ages but do see an improved cognitive performance at older ages compared to wild-type littermates.
    These published and unpublished observations provide the rationale to develop therapeutic targets for the IGF1RR407H variant to prevent or delay brain aging. There is support for IGF1R as a target for therapeutic intervention of aging. Huffman et al. [11] showed that 18-monthold female but not male mice treated with a monoclonal antibody (mAb) targeting IGF1R (L2-Cmu, Amgen Inc) had improved health span and increased median lifespan by 9 percent along with a reduction in neoplasms and inflammation compared to controls. These effects were achieved at advanced ages, suggesting that IGF1R mAbs could represent a promising therapeutic candidate to delay aging. In a second study, picropodophyllin (PDP), a selective, competitive, and reversible inhibitor of IGF1R that is brain penetrant, was given to a mouse model of AD amyloid neuropathology (APP/PS1 Tg mice) daily for 7 days IP at 1 mg/kg/day [12]. PDP attenuated levels of Aβ40 and 42 and decreased microgliosis and p-tyrosine in the hippocampus.
    Since AD is an age-related disease, drugs that prevent or slow down brain aging should also be effective in helping resist the development of AD neuropathology and the associated severe cognitive impairment. So far, there has been no single therapeutic compound that has been shown in clinical trials to have significant beneficial reversible effects even though preclinical animal studies were promising. There may be a disconnect between currently available mutant FAD mouse models and the ability to predict clinical outcomes. In most of the transgenic lines, a significant increase in APP production begins early in life possibly in utero, which may trigger consequences that alter aging and the rate of aging, and likely does not mimic the biochemical changes observed in AD. A further complication is the lack of the mixed amyloid and Tau pathology that characterizes AD. We have developed an aging mouse model of AD neuropathology using an AAVbased transfer of Aβ42 and mutant MAPT (tau P301L) [13], which allows us to test drugs in a more realistic preclinical manner. Middle-aged and older aged mice can be obtained from the United States National Institute on Aging Aged Rodent Colony and used in drug testing, without having to wait several years for young mice to age.
    Drugs can be tested in older mice over several months so different therapeutic strategies can readily be carried out. However, a high throughput drug screening system for IGF1RR407H or other IGF1R variants has yet to be developed so candidate drugs are somewhat limited. RNA sequencing could help determine whether to target specific downstream pathways. Regardless, there is a rationale for identifying drugs that target IGF1R signaling based on the beneficial aspects of significant reductions in activity at older ages. A preclinical mouse model is in place to speed up the process of moving from preclinical testing to clinical trials for treating and preventing AD (Figure 1).

    Figure 1. A hypothetical example of the effect of the IGF1RR407H variant on IGF1R signaling on a scale of 1 to 5 (low to high) in 22-month-old C57BL/6 mice with or without AAV vector-transferred Alzheimer's disease. Abbreviations: AD = AAV Aβ42+tauP301L; r407h = the IGF1R variant; Sham = AAV vector only; WT = wild-type littermates.

    Declarations

    Authors’ contributions

    All authors contributed to the writing of this manuscript.

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship

    Supported in part by NIH grants R01 AG067193 (Ladiges and Darvas, coPI’s) and R01 AG057381 (Ladiges, PI).

    Conflicts of interest

    Warren Ladiges and Martin Darvas are members Editorial Board of Aging Pathobiology and Therapeutics. The authors declare that there are no conflicts and and were not involved in the journal’s review or decisions related to this manuscript.

    References

    1. Kenyon CJ. The genetics of ageing. Erratum in: Nature, 2010, 464(7288): 504-512. [Crossref]

    2. Milman S, & Barzilai N. Dissecting the Mechanisms Underlying Unusually Successful Human Health Span and Life Span. Cold Spring Harb Perspect Med, 2015, 6(1): a025098. [Crossref]

    3. Zhang WB, Aleksic S, Gao T, Weiss EF, Demetriou E, Verghese J, et al. Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults. Cells, 2020, 9(6). [Crossref]

    4. Abdellatif M, Madeo F, Kroemer G, & Sedej S. Spermidine overrides INSR (insulin receptor)-IGF1R (insulinlike growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart. Autophagy, 2022, 18(10): 2500-2502. [Crossref]

    5. Zhang WB, Ye K, Barzilai N, & Milman S. The antagonistic pleiotropy of insulin-like growth factor 1. Aging Cell, 2021, 20(9): e13443. [Crossref]

    6. Zhao Y, Xie YZ, & Liu YS. Accelerated aging-related transcriptome alterations in neurovascular unit cells in the brain of Alzheimer’s disease. Front Aging Neurosci, 2022, 14: 949074. [Crossref]

    7. George C, Gontier G, Lacube P, François JC, Holzenberger M, & Aïd S. The Alzheimer’s disease transcriptome mimics the neuroprotective signature of IGF-1 receptordeficient neurons. Brain, 2017, 140(7): 2012-2027. [Crossref]

    8. Logan S, Pharaoh GA, Marlin MC, Masser DR, Matsuzaki S, Wronowski B et al. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes. Mol Metab, 2018, 9: 141-155. [Crossref]

    9. Tazearslan C, Huang J, Barzilai N, & Suh Y. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell, 2011, 10(3): 551-554. [Crossref]

    10. Dou Y, Darvas M, Sharma K, Mathieu J, John Morton J, Tan H, et al. Development of an IGF1R longevity variant mouse line using CRISPR/Cas9 genome editing. J Tre Bio Res, 2020.[Crossref]

    11. Mao K, Quipildor GF, Tabrizian T, Novaj A, Guan F, Walters RO, et al. Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice. Nat Commun, 2018, 9(1): 2394. [Crossref]

    12. Sohrabi M, Floden AM, Manocha GD, Klug MG, & Combs CK. IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model. Front Cell Neurosci, 2020, 14: 200. [Crossref]

    13. Darvas M, Keene D, & Ladiges W. A geroscience mouse model for Alzheimer’s disease. Pathobiol Aging Age Relat Dis, 2019, 9(1): 1616994. [Crossref]



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