Another γ-Secretase Binding Partner Implicated in Aβ Production

Scientists are seeking ways to tweak γ-secretase activity to turn down production of Aβ while leaving other substrates untouched. In the January 8 Nature Aging online, researchers led by Jee-Yin Ahn at Sungkyunkwan University School of Medicine, Suwon, South Korea, proposed a new one. They investigated ErbB3 binding protein 1 (EBP1), a ubiquitous, versatile operator in the cytoplasm. Knocking it out in cortical neurons of wild-type mice led to a buildup of Aβ; subsequently, synapses disappeared and neurons died. Conversely, overexpressing it in amyloidosis mice suppressed Aβ; memory stayed intact. This was because EBP1 bound γ-secretase’s presenilin subunit, interfering with amyloid precursor protein cleavage. This slowed Aβ generation, the authors report.

  • Eliminating EBP1 in neurons jacks Aβ production.
  • Adding EBP1 to amyloidosis models lowers it.
  • EBP1 binds presenilin, getting in the way of APP binding and cleavage.

EBP1 is low in Alzheimer’s disease brains, hinting at human relevance. “Our study suggests that … preservation of functional EBP1 could be a therapeutic strategy for AD,” the authors noted. The findings have yet to be replicated by others.

EBP1 also goes by proliferation-associated 2G4. It binds the tyrosine kinase receptor ErbB3 to activate cell growth and survival pathways. This multifunctional protein binds RNA and regulates the ribosome as well. Ahn has studied EBP1 for years, previously reporting that knockout mice die in utero due to massive cell death (Ko et al., 2019). She also uncovered roles for EBP1 in schizophrenia and neurogenesis (Hwang and Ahn, 2020; Hwang et al., 2022; Kim et al., 2024).

Plaque or No Plaque. Hippocampal neurons (blue) in 10-month-old mice lacking EBP1 (left) are besieged by amyloid plaque (red); adding back EBP1 (right) prevents this. [Courtesy of Kim et al., 2025.]

To determine what the protein does in the adult brain, joint first authors Byeong-Seong Kim and Inwoo Hwang generated conditional knockouts that lacked EBP1 expression only in forebrain neurons throughout their lifespans. By 6 months of age, these mice accumulated intracellular Aβ and, at 1 year, extracellular plaques (image at right). By that timepoint, they had also lost synapses and cortical neurons and developed memory problems. Astrogliosis started by 8 months; p-tau accumulated at 15 months. Because these pathologies develop gradually, the EBP1 conditional knockouts might better model late-onset AD than do mice carrying familial mutations, the authors suggested. For a comparison of the time course by which APP and/or presenilin transgenic mice develop signature AD pathologies, see here.

How did losing EBP1 lead to more Aβ? Assessing γ-secretase activity in brain lysates from year-old mice, the authors found that the enzyme in the conditional knockouts was similar to the levels in 5xFAD mice, and twice as active as it was in wild-type. To assess if EBP1 affects γ-secretase directly, the authors used a cultured hippocampal cell line. Overexpressing EBP1 in them suppressed Aβ production, but left untouched other γ-secretase substrates such as Notch.

Exploring the mechanism, the authors found that EBP1 bound the N-terminal tail of the presenilin subunit of γ-secretase. With EBP1 there, presenilin interacted less with APP, as per proximity ligation assay. The authors concluded that EBP1 binding gets in the way of APP.

They also report that cleavage of EBP1 by asparagine endopeptidase prevented its binding to presenilin, driving up Aβ production (Nov 2015 news). In healthy primary neuron cultures, EBP1 was endosomal; in the presence of Aβ, it moved to lysosomes. Asparagine endopeptidase also ensconces itself in lysosomes, hinting at why EBP1 levels might fall in AD brain.

To learn if EBP1 could slow amyloidosis, the scientists expressed the enzyme via viral vector injection in 1-month-old 5xFAD mice. Three months later, these mice had a third less Aβ and slightly better memory than untreated mice. When the authors expressed an uncleavable mutant of EBP1, the effects were stronger, cutting Aβ by half and further improving memory.

Does this have anything to do with people? In postmortem samples from eight AD and eight control brains, the former had half as much EBP1 as the latter. Analyzing an RNA-Seq dataset from healthy people (Liang et al., 2007), the authors found that EBP1 expression drops by about a quarter after the age of 70.

The authors suspect that falling EBP1 levels may put a person at risk of AD. Analysis of two GWAS datasets turned up associations between noncoding EBP1 variants and AD (Shigemizu et al., 2021; Bellenguez et al., 2022).—Madolyn Bowman Rogers

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References

Research Models Citations

  1. 5xFAD (B6SJL)

News Citations

  1. Does δ-Secretase Prep APP for BACE1, Boost Aβ production?

Paper Citations

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  3. Hwang I, Kim BS, Ko HR, Cho S, Lee HY, Cho SW, Ryu D, Shim S, Ahn JY. Cerebellar dysfunction and schizophrenia-like behavior in Ebp1-deficient mice. Mol Psychiatry. 2022 Apr;27(4):2030-2041. Epub 2022 Feb 15 PubMed.
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Other Citations

  1. here

Further Reading

Primary Papers

  1. Kim BS, Hwang I, Ko HR, Kim YK, Kim HJ, Seo SW, Choi Y, Lim S, Kim YK, Nie S, Ye K, Park JC, Lee Y, Jo DG, Lee SE, Kim D, Cho SW, Ahn JY. EBP1 potentiates amyloid β pathology by regulating γ-secretase. Nat Aging. 2025 Jan 8; Epub 2025 Jan 8 PubMed.

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