04 Aug 2022

Astrocytes play a pivotal role in the function of the brain, nurturing healthy synaptic function, facilitating communication between different cell types, and tending to the endless needs of neurons. But these doting cells can sour in face of persistent inflammatory insults or aging. Case in point, a study published August 1 in Nature Aging identified astrocytes engorged with vacuoles in the hippocampi of old mice. The affected cells comprised about a fifth of the astrocyte population. They struggled to transport proteins, no longer churned out their usual steady stream of synaptogenic molecules, and, on the flip side, also shirked their synaptic pruning duties.

Led by Won-Suk Chung at the Korea Advanced Institute of Science and Technology in Daejeon, the study reported that these swollen glia emerged at a younger age in a mouse model of amyloidosis. Treatment with an activator of autophagy counteracted their lethargy. The findings add to the growing number of different states that astrocytes can assume under stressful conditions.

The authors christened these distended cells autophagy-dysregulated astrocytes (APDAs). Alas, the growing list of monikers bestowed upon glial cells in different transcriptional states (think DAMs, HAMs, and MGnDs …) has prompted consensus statements urging scientists in the field to refrain from naming different subsets of astrocytes and microglia, and instead to merely describe their transcriptional, morphological, and functional attributes (July 2022 news).

What were the distinguishing characteristics of the cells spotted in this study? Co-first authors Eunbeol Lee and Yeon-Joo Jung first noticed the cells as a transcriptional cluster in a single-cell RNA-Seq analysis, which surfaced only in the hippocampi of old mice. In contrast to other astrocytes that churned out pro-inflammatory cytokines, these cells expressed an overabundance of genes involved in synaptic function.

Upon closer examination, the researchers found that the astrocytes were overloaded with vacuoles bearing autophagosome markers. These crowded vacuoles bungled protein trafficking and ensnared a host of critical astrocyte proteins, including synaptogenic factors, a receptor required for synaptic pruning, as well as the low-density lipoprotein receptor, which binds ApoE.

Neurons in close proximity to astrocytes in this clogged state tended to have fewer excitatory synapses and dendritic spines. Notably, these distended astrocytes emerged at younger ages in the hippocampi of APP/PS1 mice, where the cells showed up at 6 months of age, as opposed to 18 months in wild-type mice.

The authors were able to induce these autophagosome-stuffed astrocytes in mice by feeding them rapamycin, a pharmacological inhibitor of autophagy. Conversely, they reduced their emergence in aging mice by treating them with 3BDO, an autophagy activator and mTOR activator.—Jessica Shugart

Comments

1. • Mathias Jucker
     Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE Tübingen
   • Lary Walker
     Emory University
   • Posted: 08 Aug 2022

   These are interesting results. However, it is worth noting that such astrocytes have been described before, and some of the "vacuoles" are in fact polyglucosan bodies (Jucker et al., 1992; Jucker et al., 1994; comment on Baglietto-Vargas et al., 2021). Such astrocytic inclusions occur mainly in B6 mice and to a lesser degree in other mouse strains, and they have a strong genetic component. They tend to be sticky, and thus they can bind some antibodies non-specifically.

   Polyglucosan bodies occur in glial cells or neurons of humans; for example, corpora amylacea are astrocytic inclusions of still uncertain functional significance, and intraneuronal polyglucosan bodies are linked to rare neurodegenerative disorders such as Lafora disease and adult polyglucosan body disease (Cavanagh, 1999; Nitschke et al., 2018; Cenacchi et al., 2019). 

   Polyglucosan bodies of various types also occur naturally in a variety of animal species. The current publication now hopefully stimulates the field again to work on the nature and functional consequences of these abnormalities in the nervous system.

   References:

   Jucker M, Walker LC, Martin LJ, Kitt CA, Kleinman HK, Ingram DK, Price DL. Age-associated inclusions in normal and transgenic mouse brain. Science. 1992 Mar 13;255(5050):1443-5. PubMed.

   Jucker M, Walker LC, Schwarb P, Hengemihle J, Kuo H, Snow AD, Bamert F, Ingram DK. Age-related deposition of glia-associated fibrillar material in brains of C57BL/6 mice. Neuroscience. 1994 Jun;60(4):875-89. PubMed.

   Baglietto-Vargas D, Forner S, Cai L, Martini AC, Trujillo-Estrada L, Swarup V, Nguyen MM, Do Huynh K, Javonillo DI, Tran KM, Phan J, Jiang S, Kramár EA, Nuñez-Diaz C, Balderrama-Gutierrez G, Garcia F, Childs J, Rodriguez-Ortiz CJ, Garcia-Leon JA, Kitazawa M, Shahnawaz M, Matheos DP, Ma X, Da Cunha C, Walls KC, Ager RR, Soto C, Gutierrez A, Moreno-Gonzalez I, Mortazavi A, Tenner AJ, MacGregor GR, Wood M, Green KN, LaFerla FM. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology. Nat Commun. 2021 Apr 23;12(1):2421. PubMed.

   Cavanagh JB. Corpora-amylacea and the family of polyglucosan diseases. Brain Res Brain Res Rev. 1999 Apr;29(2-3):265-95. PubMed.

   Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA. Lafora disease - from pathogenesis to treatment strategies. Nat Rev Neurol. 2018 Oct;14(10):606-617. PubMed.

   Cenacchi G, Papa V, Costa R, Pegoraro V, Marozzo R, Fanin M, Angelini C. Update on polyglucosan storage diseases. Virchows Arch. 2019 Dec;475(6):671-686. Epub 2019 Jul 30 PubMed.

   View all comments by Mathias Jucker View all comments by Lary Walker

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References

News Citations

1. Don’t Name It: Glial States Confound Easy Labels 22 Jul 2022

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