Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with gamma-secretase and regulates neuronal amyloid beta-peptide levels

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023752%3A_____%2F17%3A43918917" target="_blank" >RIV/00023752:_____/17:43918917 - isvavai.cz</a>

Result on the web

<a href="https://alzres.biomedcentral.com/articles/10.1186/s13195-017-0279-1" target="_blank" >https://alzres.biomedcentral.com/articles/10.1186/s13195-017-0279-1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s13195-017-0279-1" target="_blank" >10.1186/s13195-017-0279-1</a>

Result language

angličtina

Original language name

Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with gamma-secretase and regulates neuronal amyloid beta-peptide levels

Original language description

Increased levels of the pathogenic amyloid beta-peptide (A beta), released from its precursor by the transmembrane protease gamma-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased in AD brain, but its role in AD pathogenesis is not known. Recent neuroimaging studies have shown that the increased MAO-B expression in AD brain starts several years before the onset of the disease. Here, we show a potential connection between MAO-B, gamma-secretase and A beta in neurons. MAO-B immunohistochemistry was performed on postmortem human brain. Affinity purification of gamma-secretase followed by mass spectrometry was used for unbiased identification of gamma-secretase-associated proteins. The association of MAO-B with gamma-secretase was studied by coimmunoprecipitation from brain homogenate, and by in-situ proximity ligation assay (PLA) in neurons as well as mouse and human brain sections. The effect of MAO-B on A beta production and Notch processing in cell cultures was analyzed by siRNA silencing or overexpression experiments followed by ELISA, western blot or FRET analysis. Methodology for measuring relative intraneuronal MAO-B and A beta 42 levels in single cells was developed by combining immunocytochemistry and confocal microscopy with quantitative image analysis. Immunohistochemistry revealed MAO-B staining in neurons in the frontal cortex, hippocampus CA1 and entorhinal cortex in postmortem human brain. Interestingly, the neuronal staining intensity was higher in AD brain than in control brain in these regions. Mass spectrometric data from affinity purified gamma-secretase suggested that MAO-B is a gamma-secretase-associated protein, which was confirmed by immunoprecipitation and PLA, and a neuronal location of the interaction was shown. Strikingly, intraneuronal A beta 42 levels correlated with MAO-B levels, and siRNA silencing of MAO-B resulted in significantly reduced levels of intraneuronal A beta 42. Furthermore, overexpression of MAO-B enhanced A beta production. This study shows that MAO-B levels are increased not only in astrocytes but also in pyramidal neurons in AD brain. The study also suggests that MAO-B regulates A beta production in neurons via gamma-secretase and thereby provides a key to understanding the relationship between MAO-B and AD pathogenesis. Potentially, the gamma-secretase/MAO-B association may be a target for reducing A beta levels using protein-protein interaction breakers.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/GBP304%2F12%2FG069" target="_blank" >GBP304/12/G069: Project of excellence in the field of neuroscience</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Alzheimers Research &amp; Therapy

ISSN

1758-9193

e-ISSN

—

Volume of the periodical

9

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

19

Pages from-to

"Article Number: 57"

UT code for WoS article

000406942500001

EID of the result in the Scopus database

2-s2.0-85026547521