ErbB3 Binding Protein 1(EBP1), Novel Modulator of PS2/γ –Secretase, Blocks PS2/ γ –Secretase Cleavage of APP, Reducing Intraneuronal Aβ Generation

Abstract

AbstractBackgroundErbB3 binding protein 1 (Ebp1) is a multifunctional protein that is involved in various cellular events including cell survival, proliferation, differentiation, and cell cycle progression either in the embryogenesis or human disease. Apart from its roles in brain development, Ebp1 may be involved in neurodegenerative diseases such as Alzheimer’s disease (AD) as its expression was plunged after birth and older brain. AD patients usually have severe synapse and neuron loss, leading to memory decline, which are also occurred in the Ebp1 deficient mice brain. We thus investigated whether alteration of Ebp1 expression affects AD pathology.Methodwe show that in AD patients’ brain and in the 5X‐FAD transgenic mice, Ebp1 level is inversely correlated with Aβ deposition and loss of Ebp1 (Ebp1flox/flox ::CaMKIIa‐Cre) or Ebp1 cleavage by AEP escalates Aβ production in vitro/ex vivo/in vivo studies.ResultForebrain deletion of ErbB3 binding protein 1(Ebp1) in mice model exerted abnormal Aβ deposition and cognitive dysfunction. Ebp1 is greatly reduced, cleaving by asparagine endopeptidase (AEP) in postmortem AD patients and 5X‐FAD mice brains. Besides prominent neuronal death and degeneration, cleaved Ebp1 N84 and N204 fragments notably escalate intraneuronal Aβ generation and aggregates with Aβ in the brain. Whereas Ebp1 associates with APP and presenilin 2 (PS2), a catalytic subunit of γ ‐secretase, protecting APP cleavage by PS2/γ‐secretase in the neuron, AEP‐mediated Ebp1 cleavage liberate blockage of PS2 access to APP in the neurons of 5X‐FAD mice. Accordingly, reinstatement of Ebp1 using AAV2‐ Ebp1 WT or uncleavable mutant expression into brain of 5X‐FAD mice improved behavioral impairment and alleviates Aβ generation.ConclusionEbp1 is a pathological substrate of AEP in AD conditions, eliciting intracellular Aβ production, blocking PS2 access to APP. Targeting APP‐PS2 interaction by non‐cleaved mutant form of Ebp1or elevating intact Ebp1 levels in AD condition may represent a novel intervention opportunity to reduce intracellular Aβ levels.