Research Paper Volume 12, Issue 1 pp 571—592

STARD1 and NPC1 expression as pathological markers associated with astrogliosis in post-mortem brains from patients with Alzheimer's disease and Down syndrome

Fabian Arenas 1, 2, , Fernanda Castro 1, 2, , Susana Nuñez 1, 2, , Gemma Gay 1, , Carmen Garcia-Ruiz 1, 2, 3, 4, , Jose C. Fernandez-Checa 1, 2, 3, 4, ,

  • 1 Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
  • 2 Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  • 3 Centro de Investigación Biomédica en Red (CIBEREHD), Barcelona, Spain
  • 4 Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA

received: July 23, 2019 ; accepted: December 23, 2019 ; published: January 5, 2020 ;

https://doi.org/10.18632/aging.102641
How to Cite

Copyright © 2020 Arenas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alzheimer´s disease (AD) is a progressive neurodegenerative disorder of complex etiology, while Down syndrome (DS) is considered a genetically determined form of AD. Alterations in cholesterol homeostasis have been linked to AD although the role in this association is not well understood. Increased expression of STARD1 and NPC1, which are involved in intracellular cholesterol trafficking, has been reported in experimental AD models but not in patients with AD. Here we analyzed endolysosomal/mitochondrial cholesterol homeostasis, expression of NPC1 and STARD1 and correlation with pathological markers of AD in cortex and hippocampus from post-mortem brains from patients with AD and DS. NPC1 expression was observed in hippocampus from patients with AD and DS. Moreover, STARD1 expression increased in hippocampus and cortex from patients with AD and DS, respectively, and its immunoreactivity discriminated controls from AD or DS with a better accuracy than Aβ42. Hippocampal areas stained with the recombinant GST-PFO probe showed increased mitochondrial cholesterol within astrocytes of brains from patients with AD and DS-brains compared to controls. Lysosomal cholesterol accumulation within hippocampal astrocytes was higher in DS than in AD. These data revealed increased intracellular cholesterol loading in hippocampus from patient with AD and DS and suggest that STARD1 could be a potential pre-clinical marker associated with early stages of AD pathology.

Abbreviations

AD: Alzheimer´s disease; Aβ42: beta amyloid peptide 42; DS: Down syndrome; EOAD: early-onset AD; LOAD: late-onset AD; mGSH: mitochondrial GSH; MAM: mitochondrial ER-associated membranes; MIM: mitochondrial inner membrane; NFTs: neurofibrillary tangles; NPC1: Niemann Pick type C1 protein; PCA: principal component analysis; PFO: recombinant perfringolysin; p-tau: phosphorylated tau; StARD1: steroidogenic acute regulatory protein.

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