Relevance of RHBDL4-mediated APP processing for Alzheimer's disease.

Autosomal dominant inherited mutations causatively link the amyloid precursor protein (APP) to Alzheimer's disease (AD) and one of its proteolytic cleavage products, Aβ peptides, is characteristic of AD. While APP's relevance in the pathogenesis of the disease is clear, its physiological functions remain poorly characterized. This is in part due to the subtle defects exhibited by APP null mice, such as decreased spine density, which hint at a role in neuronal development. Therefore, fully understanding APP's physiological functions and defining the triggers leading to Aβ production is crucial to determining the cellular conditions underlying AD. We have recently discovered an alternative processing pathway of APP mediated by the rhomboid protease RHBDL4. We have shown in vitro that RHBDL4 produces several characteristic APP fragments in the ER and affects APP cell surface levels as well as Aβ production. Here, we aim to further determine the physiological relevance of this novel pathway in the context of AD. To reveal physiological relevance in the brain, we crossed McGill-Thy1-hAPP mice with RHBDL4 null mice. Memory performance was determined through Novel object recognition (NOR) and Y maze tests on 5-month-old mice. APP and Aβ levels were measured from brain lysates by western blot and ELISA. The memory deficit observed in McGill-Thy1-hAPP mice at 5 months of age is rescued by the absence of RHBDL4. This rescue may potentially be explained by apparently lower expression of the hAPP transgene at the transcription and protein levels when RHBDL4 is absent. Likewise, Aβ levels are lower when RHBDL4 is absent, indicating a physiologically relevant role of RHBDL4 for APP. This study further confirms RHBDL4's importance for APP physiology in vivo, thus allowing the use of RHBDL4 as a new tool to further our knowledge of APP's functions. © 2021 the Alzheimer's Association.

Citation

Ylauna Christine Megane Penalva, Sherilyn Junelle Recinto, Lisa-Marie Munter. Relevance of RHBDL4-mediated APP processing for Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021 Dec;17 Suppl 3:e053878

PMID: 35108955

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