The Role of Astrocytes in Synapse Loss in Alzheimer's Disease: A Systematic Review

Overview

Journal Front Cell Neurosci

Specialty Cell Biology

Date 2022 Jul 5

PMID 35783099

Authors

Lianne A Hulshof

Danny van Nuijs

Elly M Hol

Jinte Middeldorp

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, affecting 35 million people worldwide. One pathological feature of progressing AD is the loss of synapses. This is the strongest correlate of cognitive decline. Astrocytes, as an essential part of the tripartite synapse, play a role in synapse formation, maintenance, and elimination. During AD, astrocytes get a reactive phenotype with an altered gene expression profile and changed function compared to healthy astrocytes. This process likely affects their interaction with synapses. This systematic review aims to provide an overview of the scientific literature including information on how astrocytes affect synapse formation and elimination in the brain of AD patients and in animal models of the disease. We review molecular and cellular changes in AD astrocytes and conclude that these predominantly result in lower synapse numbers, indicative of decreased synapse support or even synaptotoxicity, or increased elimination, resulting in synapse loss, and consequential cognitive decline, as associated with AD. Preventing AD induced changes in astrocytes might therefore be a potential therapeutic target for dementia. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=148278, identifier [CRD148278].

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References

Jacob C, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N . Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease. J Alzheimers Dis. 2007; 11(1):97-116. DOI: 10.3233/jad-2007-11113. View

Bazargani N, Attwell D . Astrocyte calcium signaling: the third wave. Nat Neurosci. 2016; 19(2):182-9. DOI: 10.1038/nn.4201. View

Verkerke M, Hol E, Middeldorp J . Physiological and Pathological Ageing of Astrocytes in the Human Brain. Neurochem Res. 2021; 46(10):2662-2675. PMC: 8437874. DOI: 10.1007/s11064-021-03256-7. View

Yassine H, Finch C . Alleles and Diet in Brain Aging and Alzheimer's Disease. Front Aging Neurosci. 2020; 12:150. PMC: 7297981. DOI: 10.3389/fnagi.2020.00150. View

Reichenbach N, Delekate A, Breithausen B, Keppler K, Poll S, Schulte T . P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model. J Exp Med. 2018; 215(6):1649-1663. PMC: 5987918. DOI: 10.1084/jem.20171487. View

Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991; 30(4):572-80. DOI: 10.1002/ana.410300410. View

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

Orre M, Kamphuis W, Osborn L, Jansen A, Kooijman L, Bossers K . Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Neurobiol Aging. 2014; 35(12):2746-2760. DOI: 10.1016/j.neurobiolaging.2014.06.004. View

Lorke D, Lu G, Cho E, Yew D . Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC Neurosci. 2006; 7:36. PMC: 1523198. DOI: 10.1186/1471-2202-7-36. View

10.

Choi M, Lee S, Kim D, Im H, Kim H, Jeong Y . Disruption of the astrocyte-neuron interaction is responsible for the impairments in learning and memory in 5XFAD mice: an Alzheimer's disease animal model. Mol Brain. 2021; 14(1):111. PMC: 8272251. DOI: 10.1186/s13041-021-00823-5. View

11.

Maysinger D, Ji J, Moquin A, Hossain S, Hancock M, Zhang I . Dendritic Polyglycerol Sulfates in the Prevention of Synaptic Loss and Mechanism of Action on Glia. ACS Chem Neurosci. 2017; 9(2):260-271. DOI: 10.1021/acschemneuro.7b00301. View

12.

de Pins B, Cifuentes-Diaz C, Farah A, Lopez-Molina L, Montalban E, Sancho-Balsells A . Conditional BDNF Delivery from Astrocytes Rescues Memory Deficits, Spine Density, and Synaptic Properties in the 5xFAD Mouse Model of Alzheimer Disease. J Neurosci. 2019; 39(13):2441-2458. PMC: 6435824. DOI: 10.1523/JNEUROSCI.2121-18.2019. View

13.

Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar M, Okamoto S . Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013; 110(27):E2518-27. PMC: 3704025. DOI: 10.1073/pnas.1306832110. View

14.

Guerra-Gomes S, Sousa N, Pinto L, Oliveira J . Functional Roles of Astrocyte Calcium Elevations: From Synapses to Behavior. Front Cell Neurosci. 2018; 11:427. PMC: 5776095. DOI: 10.3389/fncel.2017.00427. View

15.

Alonso A, Zaidi T, Grundke-Iqbal I, Iqbal K . Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A. 1994; 91(12):5562-6. PMC: 44036. DOI: 10.1073/pnas.91.12.5562. View

16.

Shentu Y, Hu W, Zhang Q, Huo Y, Liang J, Liuyang Z . CIP2A-promoted astrogliosis induces AD-like synaptic degeneration and cognitive deficits. Neurobiol Aging. 2018; 75:198-208. PMC: 6405315. DOI: 10.1016/j.neurobiolaging.2018.11.023. View

17.

Kamphuis W, Kooijman L, Orre M, Stassen O, Pekny M, Hol E . GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Glia. 2015; 63(6):1036-56. DOI: 10.1002/glia.22800. View

18.

Penney J, Ralvenius W, Tsai L . Modeling Alzheimer's disease with iPSC-derived brain cells. Mol Psychiatry. 2019; 25(1):148-167. PMC: 6906186. DOI: 10.1038/s41380-019-0468-3. View

19.

Shi Q, Chowdhury S, Ma R, Le K, Hong S, Caldarone B . Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017; 9(392). PMC: 6936623. DOI: 10.1126/scitranslmed.aaf6295. View

20.

Zott B, Simon M, Hong W, Unger F, Chen-Engerer H, Frosch M . A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019; 365(6453):559-565. PMC: 6690382. DOI: 10.1126/science.aay0198. View