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Shokichi Takahama, Naoki Nakaya, Stanislav I Tomarev; Olfactomedin 1 may suppress APP cleavage through its interaction with BACE1. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2959.
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Death of retinal ganglion cells (RGCs) is one of the key pathogenic features of glaucoma. The accumulation of amyloid beta (Aβ) may contribute to the RGC death. Olfactomedin 1 (Olfm1), also known as noelin and pancortin, is a secreted glycoprotein highly conserved in vertebrates. Olfm1 belongs to the family of olfactomedin domain-containing proteins, and is expressed both in the retina and brain. Available data suggest that Olfm1 may interact with amyloid precursor protein (APP), suppress its cleavage, and inhibit the subsequent production of Aβ. The mechanisms of APP cleavage inhibition by Olfm1 are unknown. Here, we investigated these mechanisms.
Primary RGS cultures were established using an immunopanning method from 1 to 5 day-old mice. Interactions between Olfm1 and putative Olfm1 binding proteins were investigated with an alkaline phosphatase fusion protein assay, as well as a co-immunoprecipitation assay using lysates of HEK293 cells transfected with corresponding expression constructs. Localization of Olfm1 and candidate proteins was investigated by immunofluorescence microscopy.
Analysis of the proteins interacting with Olfm1 confirmed binding with APP and identified beta-site amyloid precursor protein-converting enzyme (BACE1) as a novel Olfm1-binding protein. The 136 amino acid N-terminal region of Olfm1 was sufficient for its interaction with both BACE1 and APP. Olfm1 and APP were preferentially expressed in the RGC layer, while BACE1 was also expressed in the inner nuclear layer. These proteins were also detected in primary RGC cultures. Available data suggest that Olfm1-BACE1 interaction may affect the BACE1 cleavage activity with APP as a substrate.
Modulation of Olfm1-BACE1 interaction may result in the accumulation of Aβ in RGCs and brain. The N-terminal portion of Olfm1 might be considered as a potential neuroprotective agent in glaucoma and Alzheimer’s disease.
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