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Biochem Biophys Res Commun. 2018 Jan 1;495(1):533-538. doi: 10.1016/j.bbrc.2017.10.153. Epub 2017 Oct 31.

Distinct amyloid precursor protein processing machineries of the olfactory system.

Author information

1
Department of Brain and Cognitive Sciences, Graduate School, Daegu Gyeungbuk Institute of Science and Technology, Daegu, Republic of Korea.
2
Department of Brain and Cognitive Sciences, Graduate School, Daegu Gyeungbuk Institute of Science and Technology, Daegu, Republic of Korea; Convergence Research Advanced Centre for Olfaction, Daegu Gyeungbuk Institute of Science and Technology, Daegu, Republic of Korea.
3
Department of Pharmacology, School of Medicine, Gachon Medical School, Incheon, Republic of Korea.
4
Department of Brain and Cognitive Sciences, Graduate School, Daegu Gyeungbuk Institute of Science and Technology, Daegu, Republic of Korea; Convergence Research Advanced Centre for Olfaction, Daegu Gyeungbuk Institute of Science and Technology, Daegu, Republic of Korea. Electronic address: cmoon@dgist.ac.kr.

Abstract

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by β-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of β-amyloid (Aβ) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex-which contains presenilin 1 or 2 as the catalytic core-could trigger marked Aβ accumulation. Olfactory dysfunction usually occurs before the onset of typical AD-related symptoms (eg, memory loss or muscle retardation), suggesting that the olfactory system may be one of the most vulnerable regions to AD. To date however, little is known about why the olfactory system is affected so early by AD prior to other regions. Thus, we examined the distribution of secretases and levels of APP processing in the olfactory system under either healthy or pathological conditions. Here, we show that the olfactory system has distinct APP processing machineries. In particular, we identified higher expressions levels and activity of γ-secretase in the olfactory epithelium (OE) than other regions of the brain. Moreover, APP c-terminal fragments (CTF) are markedly detected. During AD progression, we note increased expression of presenilin2 of γ-secretases in the OE, not in the OB, and show that neurotoxic Aβ*56 accumulates more quickly in the OE. Taken together, these results suggest that the olfactory system has distinct APP processing machineries under healthy and pathological conditions. This finding may provide a crucial understanding of the unique APP-processing mechanisms in the olfactory system, and further highlights the correlation between olfactory deficits and AD symptoms.

KEYWORDS:

Alzheimer's disease(AD); Amyloid precursor protein(APP); Olfactory epithelium(OE); Olfactory system; Presenilin; γ-Secretase

PMID:
29097202
DOI:
10.1016/j.bbrc.2017.10.153
[Indexed for MEDLINE]

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