β-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice

Diego Piedrahita; John Fredy Castro-Alvarez; Ryan L Boudreau; Andres Villegas-Lanau; Kenneth S Kosik; Juan Carlos Gallego-Gomez; Gloria Patricia Cardona-Gómez

doi:10.3389/fncel.2015.00498

Back

β-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice

Journal article

Open access

Peer reviewed

β-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice

Diego Piedrahita, John Fredy Castro-Alvarez, Ryan L Boudreau, Andres Villegas-Lanau, Kenneth S Kosik, Juan Carlos Gallego-Gomez and Gloria Patricia Cardona-Gómez

Frontiers in cellular neuroscience, Vol.9(2016), pp.498-498

01/08/2016

DOI: 10.3389/fncel.2015.00498

PMCID: PMC4705306

PMID: 26778963

Files and links (1)

url

https://doi.org/10.3389/fncel.2015.00498View

Published (Version of record) Open Access

Abstract

β-site APP cleaving enzyme 1 (BACE1) initiates APP cleavage, which has been reported to be an inducer of tau pathology by altering proteasome functions in Alzheimer’s disease (AD). However, the exact relationship between BACE1 and PHF (Paired Helical Filaments) formation is not clear. In this study, we confirm that BACE1 and Hsc70 are upregulated in the brains of AD patients, and we demonstrate that both proteins show enhanced expression in lipid rafts from AD-affected triple transgenic mouse brains. BACE1 targeting increased Hsc70 levels in the membrane and cytoplasm fractions and downregulated Hsp90 and CHIP in the nucleus in the hippocampi of 3xTg-AD mice. However, these observations occurred in a proteasome-independent manner in vitro . The BACE1miR-induced reduction of soluble hyperphosphorylated tau was associated with a decrease in MAPK activity. However, the BACE1 RNAi-mediated reduction of hyperphosphorylated tau was only blocked by 3-MA (3-methyladenine) in vitro , and it resulted in the increase of Hsc70 and LAMP2 in lipid rafts from hippocampi of 3xTg-AD mice, and upregulation of survival and homeostasis signaling. In summary, our findings suggest that BACE1 silencing neuroprotects reducing soluble hyperphosphorylated tau, modulating certain autophagy-related proteins in aged 3xTg-AD mice.

lipid rafts

Neuroscience

tauopathy

autophagy

Alzheimer’s disease

β-secretase 1

chaperones

Details

Title: Subtitle: β-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice
Creators: Diego Piedrahita - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, University of Antioquia
John Fredy Castro-Alvarez - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, University of Antioquia
Ryan L Boudreau - Internal Medicine, University of Iowa
Andres Villegas-Lanau - Neurobank, Neuroscience Group of Antioquia, Faculty of Medicine, SIU, University of Antioquia
Kenneth S Kosik - Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara
Juan Carlos Gallego-Gomez - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, University of Antioquia
Gloria Patricia Cardona-Gómez - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, University of Antioquia
Resource Type: Journal article
Publication Details: Frontiers in cellular neuroscience, Vol.9(2016), pp.498-498
DOI: 10.3389/fncel.2015.00498
PMID: 26778963
PMCID: PMC4705306
NLM abbreviation: Front Cell Neurosci
ISSN: 1662-5102
eISSN: 1662-5102
Publisher: Frontiers Media S.A
Grant note: AG029802-01 / Fogarty International Center 111554531478; 111551928905 / Administrative Department of Science, Technology and Innovation
Language: English
Date published: 01/08/2016
Academic Unit: Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984065391202771

Metrics

16 Record Views

21 Times Cited - Web of Science

See more details