PMID- 34025357
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210526
IS  - 1662-5102 (Print)
IS  - 1662-5102 (Electronic)
IS  - 1662-5102 (Linking)
VI  - 15
DP  - 2021
TI  - Beta-Secretase 1 Underlies Reactive Astrocytes and Endothelial Disruption in 
      Neurodegeneration.
PG  - 656832
LID - 10.3389/fncel.2021.656832 [doi]
LID - 656832
AB  - Dysfunction in the neurovascular unit (NVU) is a key component in the progressive 
      deterioration of Alzheimer's disease (AD) and is critical in vascular dementia. 
      Recent studies have shown that inflammation plays early and perhaps causal roles 
      in the pathogenesis of AD related to NVU damage, possibly in part by 
      overactivating the aspartic acid protease activity of beta-site amyloid precursor 
      protein-cleaving enzyme 1 (BACE1), which until now has almost solely been studied 
      in the context of the beta-amyloid cascade. In this study, we analyzed the 
      relationship of BACE1 with astrocytes and blood vessels in human brains with 
      sporadic and familial dementia [Autosomal dominant cerebral arteriopathy with 
      subcortical infarcts and leukoencephalopathy (CADASIL), sporadic Alzheimer's 
      disease (SAD), and familial Alzheimer's disease (FAD)] and how BACE1 inhibition 
      affects astrocytes and endothelial cells under conditions of glutamate toxicity. 
      Our results show increased BACE1, PHF (Paired helical filaments)-tau and GFAP 
      (Glial Fibrillary Acid Protein) immunoreactivity (IR) in the CA1 hippocampal 
      regions of FAD and SAD brains. Furthermore, BACE1 immunoprecipitated with GFAP in 
      tissue samples from all study cases, but their immunofluorescence close to (10 
      mum(3)) or overlapping blood vessels was only increased in FAD and SAD brains, and 
      PHF-tau was present around the vessels mainly in FAD brains. Interestingly, the 
      increased BACE1 levels were associated with reactive astrocytes, characterized by 
      morphological changes and upregulation of GFAP under pathological and stressful 
      conditions, and endothelial disruption by glutamate excitotoxicity, and these 
      effects were reversed by BACE1 inhibition; further, BACE1-inhibited astrocytes 
      protected endothelial cell integrity by preserving zonula occludens-1 (ZO-1) 
      distribution and decreasing the expression of inflammatory markers. Taken 
      together, these findings suggest that BACE1 dysregulation in astrocytes may have 
      a role in the alterations in NVU integrity implicated in neurodegeneration.
CI  - Copyright (c) 2021 Chacon-Quintero, Pineda-Lopez, Villegas-Lanau, Posada-Duque and 
      Cardona-Gomez.
FAU - Chacon-Quintero, Maria Victoria
AU  - Chacon-Quintero MV
AD  - Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, 
      Cellular and Molecular Neurobiology Area, Medellin, Colombia.
AD  - Institute of Biology, Faculty of Exact and Natural Sciences, University of 
      Antioquia, Medellin, Colombia.
FAU - Pineda-Lopez, Lina Gisela
AU  - Pineda-Lopez LG
AD  - Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, 
      Cellular and Molecular Neurobiology Area, Medellin, Colombia.
AD  - Institute of Biology, Faculty of Exact and Natural Sciences, University of 
      Antioquia, Medellin, Colombia.
FAU - Villegas-Lanau, Carlos Andres
AU  - Villegas-Lanau CA
AD  - Neurobank, Faculty of Medicine, SIU, University of Antioquia, Medellin, Colombia.
FAU - Posada-Duque, Rafael
AU  - Posada-Duque R
AD  - Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, 
      Cellular and Molecular Neurobiology Area, Medellin, Colombia.
AD  - Institute of Biology, Faculty of Exact and Natural Sciences, University of 
      Antioquia, Medellin, Colombia.
FAU - Cardona-Gomez, Gloria Patricia
AU  - Cardona-Gomez GP
AD  - Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, 
      Cellular and Molecular Neurobiology Area, Medellin, Colombia.
LA  - eng
PT  - Journal Article
DEP - 20210506
PL  - Switzerland
TA  - Front Cell Neurosci
JT  - Frontiers in cellular neuroscience
JID - 101477935
PMC - PMC8136516
OTO - NOTNLM
OT  - BACE1
OT  - endothelial disruption
OT  - neurodegeneration
OT  - neurovascular unit
OT  - reactive astrocytes
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/05/25 06:00
MHDA- 2021/05/25 06:01
PMCR- 2021/01/01
CRDT- 2021/05/24 08:03
PHST- 2021/01/21 00:00 [received]
PHST- 2021/04/12 00:00 [accepted]
PHST- 2021/05/24 08:03 [entrez]
PHST- 2021/05/25 06:00 [pubmed]
PHST- 2021/05/25 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fncel.2021.656832 [doi]
PST - epublish
SO  - Front Cell Neurosci. 2021 May 6;15:656832. doi: 10.3389/fncel.2021.656832. 
      eCollection 2021.