Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA.
Normal aging induces A1-like astrocyte reactivity.
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1896-E1905. Epub 2018 Feb 7
PubMed.
Aging is associated with marked changes in brain function and is the biggest risk factor for the development of neurodegenerative diseases. Glial cells in the brain, including astrocytes, are the first responders to most types of stress, and thus it is important to characterize how they may change their properties with age. These two studies examine the changes in astrocyte gene expression between young and aged mice (equivalent perhaps to a 70-year-old human). Both agree on two key findings: 1) that different brain regions age in somewhat different ways, and 2) that aging, in general, is associated with similar gene expression changes as seen in reactive astrocytes—the type of astrocytes elicited after brain injury. Differences in the techniques used to purify transcripts in these two papers could account for some variation in results, but in general, these should serve as good resources to better understand how astrocyte functions change with age. A major question is the extent to which these gene expression changes correlate with changes in astrocyte functions, and whether those functions preserve or exacerbate age-related declines in brain health.
Over the past year, the nature of astrocyte diversity has emerged as a hot topic in the field of glial biology, with several papers describing both regional differences and distinct subpopulations in the normal brain (Chai et al., 2017; Morel et al., 2017; John Lin et al., 2017). Leveraging this knowledge, the two papers covered in this news story take the very important next steps and assess how region-specific astrocytes evolve over the course of aging.
These are very important observations, as they show that astrocytes have a form of “plasticity”—meaning that they are not static populations of “glue,” but rather exhibit a previously underappreciated responsiveness to their surrounding environment. These are indeed exciting times to be an astrocyte biologist, as these findings, coupled with the aforementioned studies that elucidated diverse astrocyte populations, point to the possibility that unique astrocyte "subpopulations" or "states” demonstrate disease-specific associations.
That the astrocytes found in the aged brain demonstrate immune “fingerprints” implicates them in aging-related brain disorders, like Alzheimer’s disease. Nevertheless, the prospective link between changed astrocytes in aging and bona fide degenerative disorders remains correlative, as much work remains to demonstrate actual causation. Admittedly, this is a major challenge because the cause-and-effect relationships between immune cells, astrocytes, neurons, and endothelial cells is not linear, but rather a web of interdependencies that occurs across equally complex and diverse degenerative disease states.
In sum, these are very important first steps in understanding how astrocytes evolve and how this evolution may facilitate the onset of aging-related disorders.
References:
Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC, Yu X, Cohn W, Rajendran PS, Vondriska TM, Whitelegge JP, Coppola G, Khakh BS.
Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence.
Neuron. 2017 Aug 2;95(3):531-549.e9. Epub 2017 Jul 14
PubMed.
Morel L, Chiang MS, Higashimori H, Shoneye T, Iyer LK, Yelick J, Tai A, Yang Y.
Molecular and Functional Properties of Regional Astrocytes in the Adult Brain.
J Neurosci. 2017 Sep 6;37(36):8706-8717. Epub 2017 Aug 7
PubMed.
John Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Zhang Y, Zhu W, Mohila CA, Ahmed N, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, Deneen B.
Identification of diverse astrocyte populations and their malignant analogs.
Nat Neurosci. 2017 Mar;20(3):396-405. Epub 2017 Feb 6
PubMed.
These papers provide useful information and an important resource. They also add further weight to the idea of a spectrum of astrocyte phenotypes, much like what has gradually appreciated with microglia ... which are not just active or resting, or even M1 or M2.
Even during robust neurodegeneration, “reactive” astrocytes are not making their full secretory profile. We demonstrated “priming” of astrocytes, during neurodegeneration, to respond in an exaggerated fashion to acute cytokine stimulation (Hennessy et al., 2015). It will interesting to see to what extent this is true in aging and other degenerative models.
References:
Hennessy E, Griffin ÉW, Cunningham C.
Astrocytes Are Primed by Chronic Neurodegeneration to Produce Exaggerated Chemokine and Cell Infiltration Responses to Acute Stimulation with the Cytokines IL-1β and TNF-α.
J Neurosci. 2015 Jun 3;35(22):8411-22.
PubMed.
Comments
UCSF Weill Institute for Neurosciences, University of California, San Francisco
Aging is associated with marked changes in brain function and is the biggest risk factor for the development of neurodegenerative diseases. Glial cells in the brain, including astrocytes, are the first responders to most types of stress, and thus it is important to characterize how they may change their properties with age. These two studies examine the changes in astrocyte gene expression between young and aged mice (equivalent perhaps to a 70-year-old human). Both agree on two key findings: 1) that different brain regions age in somewhat different ways, and 2) that aging, in general, is associated with similar gene expression changes as seen in reactive astrocytes—the type of astrocytes elicited after brain injury. Differences in the techniques used to purify transcripts in these two papers could account for some variation in results, but in general, these should serve as good resources to better understand how astrocyte functions change with age. A major question is the extent to which these gene expression changes correlate with changes in astrocyte functions, and whether those functions preserve or exacerbate age-related declines in brain health.
View all comments by Anna Victoria MolofskyBaylor College of Medicine
Over the past year, the nature of astrocyte diversity has emerged as a hot topic in the field of glial biology, with several papers describing both regional differences and distinct subpopulations in the normal brain (Chai et al., 2017; Morel et al., 2017; John Lin et al., 2017). Leveraging this knowledge, the two papers covered in this news story take the very important next steps and assess how region-specific astrocytes evolve over the course of aging.
These are very important observations, as they show that astrocytes have a form of “plasticity”—meaning that they are not static populations of “glue,” but rather exhibit a previously underappreciated responsiveness to their surrounding environment. These are indeed exciting times to be an astrocyte biologist, as these findings, coupled with the aforementioned studies that elucidated diverse astrocyte populations, point to the possibility that unique astrocyte "subpopulations" or "states” demonstrate disease-specific associations.
That the astrocytes found in the aged brain demonstrate immune “fingerprints” implicates them in aging-related brain disorders, like Alzheimer’s disease. Nevertheless, the prospective link between changed astrocytes in aging and bona fide degenerative disorders remains correlative, as much work remains to demonstrate actual causation. Admittedly, this is a major challenge because the cause-and-effect relationships between immune cells, astrocytes, neurons, and endothelial cells is not linear, but rather a web of interdependencies that occurs across equally complex and diverse degenerative disease states.
In sum, these are very important first steps in understanding how astrocytes evolve and how this evolution may facilitate the onset of aging-related disorders.
References:
Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC, Yu X, Cohn W, Rajendran PS, Vondriska TM, Whitelegge JP, Coppola G, Khakh BS. Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence. Neuron. 2017 Aug 2;95(3):531-549.e9. Epub 2017 Jul 14 PubMed.
Morel L, Chiang MS, Higashimori H, Shoneye T, Iyer LK, Yelick J, Tai A, Yang Y. Molecular and Functional Properties of Regional Astrocytes in the Adult Brain. J Neurosci. 2017 Sep 6;37(36):8706-8717. Epub 2017 Aug 7 PubMed.
John Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Zhang Y, Zhu W, Mohila CA, Ahmed N, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, Deneen B. Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci. 2017 Mar;20(3):396-405. Epub 2017 Feb 6 PubMed.
View all comments by Benjamin DeneenTrinity College Dublin
These papers provide useful information and an important resource. They also add further weight to the idea of a spectrum of astrocyte phenotypes, much like what has gradually appreciated with microglia ... which are not just active or resting, or even M1 or M2.
Even during robust neurodegeneration, “reactive” astrocytes are not making their full secretory profile. We demonstrated “priming” of astrocytes, during neurodegeneration, to respond in an exaggerated fashion to acute cytokine stimulation (Hennessy et al., 2015). It will interesting to see to what extent this is true in aging and other degenerative models.
References:
Hennessy E, Griffin ÉW, Cunningham C. Astrocytes Are Primed by Chronic Neurodegeneration to Produce Exaggerated Chemokine and Cell Infiltration Responses to Acute Stimulation with the Cytokines IL-1β and TNF-α. J Neurosci. 2015 Jun 3;35(22):8411-22. PubMed.
View all comments by Colm CunninghamMake a Comment
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