Reduction of β-amyloid accumulation by reticulon 3 in transgenic mice.

Abstract

Inhibition of the β-secretase, BACE1, which cleaves amyloid precursor protein (APP) to produce β-amyloid protein (Aβ), is thought to be a feasible therapeutic strategy for Alzheimer's disease. Reticulon (RTN) proteins such as RTN3 have been identified as membrane proteins that interact with BACE1 and inhibit its Aβ-generating activity. In this study, we investigated whether RTN3 can regulate Aβ production in vivo, using transgenic (Tg) mice expressing APP with Swedish and London mutations (APP Tg mice) and those expressing RTN3; the latter mice showed ~1.4-fold higher expression levels of RTN3 protein in the cerebral cortex than non-Tg controls. We analyzed the brains of single APP Tg and double APP/RTN3 Tg mice at the age of approximately 15 months. The levels of secreted APP-β, a direct BACE1 cleavage product of APP, in Tris-soluble fraction were considerably reduced in the hippocampus and cerebral cortex of APP/RTN3 Tg mice relative to those in APP Tg mice. Immunohistochemical analyses demonstrated that Aβ burden and plaques were significantly (by approximately 50%) decreased in both the hippocampus and cerebral cortex of double Tg mice compared to APP Tg mice. Furthermore, the levels of guanidine-soluble Aβ40 and Aβ42 in these brain regions of APP/RTN3 Tg mice were relatively lower than those in APP Tg mice. These findings indicate that even a small increase in RTN3 expression exerts suppressive effects on amyloidogenic processing of APP and Aβ accumulation through modulation of BACE1 activity in vivo, and suggest that induction of RTN3 might be an effective therapeutic strategy against Alzheimer's disease.

• Authors: Wataru Araki, Akiko Oda, Kazumi Motoki, Kotaro Hattori, Masayuki Itoh, Shigeki Yuasa, Yoshihiro Konishi, Ryong-Woon Shin, Akira Tamaoka, Koichi Ogino
• Journal: Current Alzheimer research (Curr Alzheimer Res) Vol. 10 Issue 2 Pg. 135-42 (Feb 2013) ISSN: 1875-5828 [Electronic] United Arab Emirates
• PMID: 22742855 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Carrier Proteins
• Membrane Proteins
• Nerve Tissue Proteins
• Peptide Fragments
• RTN3 protein, human
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• BACE1 protein, human

Topics

• Alzheimer Disease (genetics, metabolism)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Aspartic Acid Endopeptidases (metabolism)
• Carrier Proteins (genetics)
• Disease Models, Animal
• Gene Expression Regulation (genetics)
• Humans
• Membrane Proteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Tissue Proteins (genetics)
• Peptide Fragments (metabolism)