Studies on Proteolytic Processing of Amyloid Precursor protein (APP) in Olfactory Epithelium using AD Transgenic Mice

Abstract

Olfactory impairment is a well-documented abnormality in Alzheimer’s disease (AD). AD is known to begin with abnormal processing of amyloid precursor protein (APP), through sequen-tial cleavages first by β-secretase and then by γ-secretase complex which leads to excess produc-tion of β-amyloid (Aβ) in the cortex. While olfactory dysfunction occurs in the incipient stages of AD even before Aβ deposition and plaque formation in the CNS, the functional correlation of olfac-tory deficit in relation to AD is not well understood. It may be critical to know the process under-lying AD-related olfactory sensory loss to find some novel biomarkers. To this end, two different types of transgenic mice models were used including Tg2576, which overexpresses human APP and Tg6799 (also called 5xFAD), which expresses human APP and Presenilin1 both mutations to-gether. It was found unique APP processing in OE that has significance in providing not only pos-sible biomarkers that can be used for screening and detection of AD before plaque formation but also for treatment purposes. This data demonstrates that the abnormal processing of APP in the OE provides APP fragments including 25 kDa, 55kDa and 80 kDa that can be a potential biomarker in the very early and critical period in the stage of mild cognitive impairment, that is, the critical stage of AD occurrence (before Aβ plaque formation in the CNS). Such biomarkers can be accessed via biopsy and can be used for establishing improved early diagnostic procedure for the AD. Additionally, PS2 increased level was found in OE that possibly involved in unique APP processing and might also be crucial for under-standing the γ-secretase role controlling AD through γ-secretase as a therapeutic target. ⓒ 2014 DGIST