Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer’s disease mouse model

作者：Ylauna Christine Mégane Penalva, Sandra Paschkowsky, Jingyun Yang, Sherilyn Junelle Recinto, Jessica Cinkornpumin, Marina Ruelas, Bin Xiao, Albert Nitu, Sin Young Kwon, Helen Yee-Li Wu, Hans Markus Münter, Bernadeta Michalski, Margaret Fahnestock, William A. Pastor, David A. Bennett, Lisa Marie Munter · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07579-z · 被引用次数：6 · 研究领域：Alzheimer's disease research and treatments、Nuclear Receptors and Signaling、Macrophage Migration Inhibitory Factor

Abstract Characteristic cerebral pathological changes of Alzheimer’s disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as Aβ peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation. We demonstrated previously that RHBDL4 cleaves APP in HEK293T cells, leading to decreased total APP and Aβ. More recently, we showed that RHBDL4 processes APP in mouse primary mixed cortical cultures as well. Here, we aim to examine the physiological relevance of RHBDL4 in the brain. We first found that brain samples from AD patients and an AD mouse model (APPtg) showed increased RHBDL4 mRNA and protein expression. To determine the effects of RHBDL4’s absence on APP physiology in vivo, we crossed APPtg mice to a RHBDL4 knockout (R4 −/− ) model. RHBDL4 deficiency in APPtg mice led to increased total cerebral APP and amyloidogenic processing when compared to APPtg controls. Contrary to expectations, as assessed by cognitive tests, RHBDL4 absence rescued cognition in 5-month-old female APPtg mice. Informed by unbiased RNA-seq data, we demonstrated in vitro and in vivo that RHBDL4 absence leads to greater levels of active β-catenin due to decreased proteasomal clearance. Decreased β-ca...