Hannah Whittaker

Background: Alzheimer’s disease (AD) is the most common form of dementia characterized by the decline of memory and cognitive function, eventually leading to profound dementia and death.^1­ The two classical pathological features of AD are extracellular amyloid plaques and intraneuronal neurofibrillary tangles (NFTs) comprising phosphorylated tau protein in the brain.² Amyloid plaques are generated by the aggregation of toxic soluble Αβ-42 oligomers. In the hippocampus, the toxic oligomers trigger hyperactivity of astrocytes through specific cell surface receptors such as erythropoietin-producing hepatocellular A4 (EphA4).³ EphA4 then stimulates astrocytes to phagocytize excitatory synapses through the complement cascade. This creates the early stages of AD and mild cognitive impairment (MCI).^1,3 Currently, there are only drugs available to relieve symptoms of AD with no curative effect.^4,5 It has been found that pathological changes caused by AD begin 20 years before the onset of symptoms. Thus, early diagnosis and treatment of AD could dramatically affect patient outcomes.⁴ Furthermore, the signaling pathways that connect Αβ Oligomers to hippocampal synapse loss are not entirely understood. However, the current research being conducted on the EphA4 signaling pathway could provide answers as well as an early therapeutic target for AD.¹

Objective: This review aims to explore the effects of EphA4 inhibition on AD and identify potential therapies for AD through EphA4 inhibition.

Search Methods: Using the PubMed database, an online search was conducted between 2017 and 2025 using the key words “Receptor, EphA4” and “Alzheimer’s”.

Results: In a healthy individual, the EphA4 signaling pathway activates astrocytes to phagocytose excitatory synapses in the hippocampus to maintain homeostasis.³­­­­­­ In mouse models of AD, studies have reported increased expression of EphA4 in the hippocampus compared to wildtype mice, indicating a dysregulation of EphA4 expression in AD. ^3,6,7­ Furthermore, in AD mice, it was found that deletion of EphA4 increased excitatory synapse density, mature spine density, and the number of action potentials and basal synaptic transmission.³ EphA4 inhibition was also found to decrease the metabolic state of astrocytes and their hyperactivity through decreased oxidative phosphorylation, ATP synthesis, and cytosolic volume.³ Deleting EphA4 also decreases C3⁺ and CD44⁺ astrocytes and reduces C1q levels, thus decreasing astrocyte immunoreactivity and astrocyte engulfment of excitatory synapses via complement.³ In addition, another group found that EphA4 inhibition in AD mice improves social memory loss through increased hippocampal dendritic spine length and head width.⁷ Seeing that EphA4 plays a key role in the pathogenesis of AD, a research group generated two nanobodies, Nb 39 and Nb 53, as potential AD therapeutics that selectively inhibit the EphA4 receptor.⁸ Likewise, another group computationally screened FDA-approved drugs and found five that selectively inhibit EphA4, which may be repurposed or used in developing new AD treatments.⁹

Conclusion: Studies have shown that cognitive impairment in AD is associated with significant hippocampal synapse loss and astrocyte malfunction, which may be attributed to active EphA4 signaling.³ Additionally, EphA4 inhibition reduces and restores many of the pathogenic effects of AD and improves social memory loss, making it a potential therapeutic target.^3,7 Although no human studies have been conducted, nanobodies and five FDA-approved drugs have been shown to selectively inhibit EphA4, making them promising candidates for the development of AD therapeutics.^8,9

Works Cited:

1. Vargas LM, Cerpa W, Muñoz FJ, Zanlungo S, Alvarez AR. Amyloid-β oligomers synaptotoxicity: The emerging role of EphA4/c-Abl signaling in Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt A):1148-1159. doi:10.1016/j.bbadis.2018.01.023
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;56(9):5532-5546. doi:10.1111/ejn.15591
3. Yang X, Wang Y, Qiao Y, et al. Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2025;122(7):e2420324122. doi:10.1073/pnas.2420324122
4. Jucker M, Walker LC. Alzheimer’s disease: From immunotherapy to immunoprevention. Cell. 2023;186(20):4260-4270. doi:10.1016/j.cell.2023.08.021
5. Khan S, Barve KH, Kumar MS. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr Neuropharmacol. 2020;18(11):1106-1125. doi:10.2174/1570159X18666200528142429
6. Liang Y, Raven F, Ward JF, et al. Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo. J Alzheimers Dis. 2020;76(3):1071-1082. doi:10.3233/JAD-200128
7. Poppe L, Rué L, Timmers M, et al. EphA4 loss improves social memory performance and alters dendritic spine morphology without changes in amyloid pathology in a mouse model of Alzheimer’s disease. Alzheimers Res Ther. 2019;11(1):102. Published 2019 Dec 12. doi:10.1186/s13195-019-0554-4
8. Schoonaert L, Rué L, Roucourt B, et al. Identification and characterization of Nanobodies targeting the EphA4 receptor. J Biol Chem. 2017;292(27):11452-11465. doi:10.1074/jbc.M116.774141
9. Gu S, Fu WY, Fu AKY, et al. Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs. Sci Rep. 2018;8(1):7377. Published 2018 May 9. doi:10.1038/s41598-018-25790-1