07 Mar 2025

Astrocytes are notoriously two-faced—calmly coddling neurons one minute, then ruthlessly consuming their synapses the next. Why these dramatic mood swings? Blame the EphA4 receptor, according to a study published February 18 in Proceedings of the National Academy of Sciences. Using inhibitor and conditional knockout approaches, scientists led by Nancy Ip of the Hong Kong University of Science and Technology found that expression of EphA4, a receptor tyrosine kinase and AD risk factor, rises in both neurons and astrocytes as amyloidosis sets in. In astrocytes, it promotes reactivity and activation of the complement cascade, which turns the cells against synapses. Inhibiting EphA4, or knocking it out of astrocytes, stemmed this destructive behavior, sparing synapses. The findings might help explain how EphA4 influences AD risk.

Erythropoietin-producing hepatocellular (Eph) receptors, including EphA4, are expressed on the cell surface and involved in brain development, which involves extensive pruning of synapses. A variant in EphA4 increases a person’s odds of getting AD (Shen et al., 2010; Ganguly et al., 2022).

Alas, why it does that is unclear, with some studies identifying beneficial functions, such as dampening Aβ production in neurons (Tamura et al., 2020), while others, including from Ip’s group, have cast the receptor as a synaptic henchman. Specifically, they demonstrated that EphA4 expression in neurons promotes the retraction of dendritic spines and degradation of AMPA receptors, and exacerbates synaptic loss in AD mouse models (Dec 2006 news; Fu et al., 2014; Vargas et al., 2014). In AD, glia are known to take part in synaptic destruction, via complement-mediated pruning (Dec 2014 news; Jan 2017 news). Might EphA4 promote this glia-driven synaptic loss, too?

In their new study, first author Xin Yang and colleagues addressed this question in the hippocampi of APP/PS1 mice. They found that in the CA1 region, EphA4 expression increased in both pyramidal neurons and in astrocytes as amyloidosis worsened and the number of synapses fell. This was prevented by treating these PS1 mice with KYL, a 12-amino acid peptide that inhibits EphA4 (Murai et al., 2003). This biologically active peptide also bolstered the density of dendritic spines on CA1 neurons, which are known to house excitatory synapses. According to electrophysiological experiments, blocking EphA4 restored full-strength synaptic transmission in CA1 synapses, which flagged in untreated APP/PS1 mice.

The scientists deployed single-cell RNA-Seq to tease apart these effects. They found that CA1 neurons in APP/PS1 mice ramped up expression of genes involved in oxidative stress, apoptosis, and cytoskeleton organization. Treatment with KYL restored expression of these genes to wild-type levels and rescued synapses, suggesting that EphA4 may have goaded synaptic destruction via these mechanisms in neurons. As for astrocytes, three subsets emerged. One expressed high levels of EphA4 along with genes involved in astrocyte reactivity, phagocytosis, and synapse elimination. The latter included the complement protein C3, a downstream effector of the microglial-derived C1q protein, as well as CD44, a surface receptor for C1q. Notably, KYL counteracted this reactive profile, dousing expression of complement genes.

Astrocytes prune synapses decorated with C1q, and this has been implicated in synaptic degeneration in AD. This was in full swing in the hippocampi of APP/PS1 mice, as evidenced by C1q-studded synapses and bulging, reactive astrocytes stuffed with synaptic proteins. EphA4 inhibition counteracted both astrocyte reactivity and synaptic engulfment.

EphA4 expression rose in both neurons and astrocytes with worsening amyloidosis, but was neuronal or astrocytic EphA4 causing the trouble? Yang addressed this question with conditional knockouts. Knocking out EphA4 from either cell type in APP/PS1 mice spared both synapses and mature dendritic spines. Sans EphA4, astrocytes were not reactive and engulfed fewer synapses.

The findings suggest that EphA4-driven synaptic engulfment by astrocytes is one of several ways that synapses crumble in AD, Ip wrote to Alzforum. “It is challenging to assess the contribution of astrocytic EphA4 to synapse loss in AD, relative to other mechanisms,” she wrote, noting that other pathways, including glial complement signaling, microglial TREM2 signaling, and astrocytic Megf10 and Mertk signaling reportedly take part in the destruction (Apr 2016 news; Dec 2013 conference news on Chung et al., 2013; Dejanovic et al., 2022).

“The age-dependent change of EphA4 levels within astrocytes may serve as a risk factor for AD, leading to astrocytic dysfunction and exacerbating their engulfment of excitatory synapses,” Ip wrote.—Jessica Shugart

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. What Drives Dendritic Spine Loss? Study Taps Cdk5 2 Dec 2006
2. Neurons Cave When Astrocytes Heap on the Complements 22 Dec 2014
3. Microglia Give Astrocytes License to Kill 20 Jan 2017
4. Paper Alert: Microglia Mediate Synaptic Loss in Early Alzheimer’s Disease 1 Apr 2016
5. Glial Cells Refine Neural Circuits 5 Dec 2013

Research Models Citations

1. APPswe/PSEN1dE9 (line 85)

Paper Citations

1. Shen L, Kim S, Risacher SL, Nho K, Swaminathan S, West JD, Foroud T, Pankratz N, Moore JH, Sloan CD, Huentelman MJ, Craig DW, Dechairo BM, Potkin SG, Jack CR, Weiner MW, Saykin AJ, . Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort. Neuroimage. 2010 Nov 15;53(3):1051-63. PubMed.
2. Ganguly D, Thomas JA, Ali A, Kumar R. Mechanistic and therapeutic implications of EphA-4 receptor tyrosine kinase in the pathogenesis of Alzheimer's disease. Eur J Neurosci. 2022 Jan 5; PubMed.
3. Tamura K, Chiu YW, Shiohara A, Hori Y, Tomita T. EphA4 regulates Aβ production via BACE1 expression in neurons. FASEB J. 2020 Dec;34(12):16383-16396. Epub 2020 Oct 22 PubMed.
4. Fu AK, Hung KW, Huang H, Gu S, Shen Y, Cheng EY, Ip FC, Huang X, Fu WY, Ip NY. Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer's disease. Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9959-64. Epub 2014 Jun 23 PubMed.
5. Vargas LM, Leal N, Estrada LD, González A, Serrano F, Araya K, Gysling K, Inestrosa NC, Pasquale EB, Alvarez AR. EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers. PLoS One. 2014;9(3):e92309. Epub 2014 Mar 21 PubMed.
6. Murai KK, Nguyen LN, Koolpe M, McLennan R, Krull CE, Pasquale EB. Targeting the EphA4 receptor in the nervous system with biologically active peptides. Mol Cell Neurosci. 2003 Dec;24(4):1000-11. PubMed.
7. Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, Joung J, Foo LC, Thompson A, Chen C, Smith SJ, Barres BA. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013 Dec 19;504(7480):394-400. Epub 2013 Nov 24 PubMed.
8. Dejanovic B, Wu T, Tsai MC, Graykowski D, Gandham VD, Rose CM, Bakalarski CE, Ngu H, Wang Y, Pandey S, Rezzonico MG, Friedman BA, Edmonds R, De Mazière A, Rakosi-Schmidt R, Singh T, Klumperman J, Foreman O, Chang MC, Xie L, Sheng M, Hanson JE. Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models. Nat Aging. 2022 Sep;2(9):837-850. Epub 2022 Sep 20 PubMed.

Further Reading

News

1. Do Tribes of Astrocytes Wage War on Synapses? 5 Apr 2019