Soluble form of the APP fragment, sAPPβ, positively regulates tau secretion

Haruaki Sato; Kensaku Kasuga; Noriko Isoo; Toshihiro Hayashi; Takeshi Ikeuchi; Yukiko Hori; Taisuke Tomita

doi:10.1016/j.neures.2023.03.002

Soluble form of the APP fragment, sAPPβ, positively regulates tau secretion

Neurosci Res. 2023 Aug:193:63-70. doi: 10.1016/j.neures.2023.03.002. Epub 2023 Mar 24.

Authors

Haruaki Sato¹, Kensaku Kasuga², Noriko Isoo³, Toshihiro Hayashi³, Takeshi Ikeuchi², Yukiko Hori⁴, Taisuke Tomita⁵

Affiliations

¹ Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
² Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
³ Department of Physiology, School of Medicine, Teikyo University, Tokyo, Japan.
⁴ Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: yukiko-hori@mol.f.u-tokyo.ac.jp.
⁵ Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: taisuke@mol.f.u-tokyo.ac.jp.

PMID: 36967088
DOI: 10.1016/j.neures.2023.03.002

Abstract

Extracellular tau has been highlighted in the pathogenesis of Alzheimer disease (AD), which is the most common neurodegenerative disease. Pathological analyses as well as model animal studies suggest that amyloid-β peptide (Aβ) deposition facilitates the spreading of tau aggregation pathology via extracellular tau. However, the precise mechanism of tau secretion remains unknown. Here, we show that the overexpression of amyloid precursor protein (APP) enhances the secretion of tau phosphorylated at threonine 181 in mouse neuroblastoma Neuro2a cells. Moreover, we found that soluble amyloid precursor protein β (sAPPβ), which is generated by β-site APP cleaving enzyme 1 (BACE1), mediates tau secretion. Our results demonstrate that BACE1-mediated cleavage of APP plays pathological roles in AD pathogenesis by not only Aβ production, but by the spreading of tau aggregation pathology via sAPPβ in AD patients.

Keywords: APP processing; Alzheimer disease; Phosphorylated tau; Soluble amyloid precursor protein; Tau secretion.

MeSH terms

Alzheimer Disease* / metabolism
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / metabolism
Animals
Aspartic Acid Endopeptidases / metabolism
Mice
Neurodegenerative Diseases*
tau Proteins / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
tau Proteins
Mapt protein, mouse
APP protein, mouse