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Higher levels of kallikrein-8 in female brain may increase the risk for Alzheimer's disease.

Authors
  • Keyvani, Kathy1
  • Münster, Yvonne1
  • Kurapati, Nirup K1
  • Rubach, Sebastian1
  • Schönborn, Andreas1
  • Kocakavuk, Emre1
  • Karout, Mohamed1
  • Hammesfahr, Pia1
  • Wang, Ya-Chao2
  • Hermann, Dirk M2
  • Teuber-Hanselmann, Sarah1
  • Herring, Arne1
  • 1 Institute of Neuropathology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. , (Germany)
  • 2 Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. , (Germany)
Type
Published Article
Journal
Brain Pathology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Nov 01, 2018
Volume
28
Issue
6
Pages
947–964
Identifiers
DOI: 10.1111/bpa.12599
PMID: 29505099
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Women seem to have a higher vulnerability to Alzheimer's disease (AD), but the underlying mechanisms of this sex dichotomy are not well understood. Here, we first determined the influence of sex on various aspects of Alzheimer's pathology in transgenic CRND8 mice. We demonstrate that beta-amyloid (Aβ) plaque burden starts to be more severe around P180 (moderate disease stage) in female transgenics when compared to males and that aging aggravates this sex-specific difference. Furthermore, we show that female transgenics suffer from higher levels of neurovascular dysfunction around P180, resulting in impaired Aβ peptide clearance across the blood-brain-barrier at P360. Female transgenics show also higher levels of diffuse microgliosis and inflammation, but the density of microglial cells surrounding Aβ plaques is less in females. In line with this finding, testosterone compared to estradiol was able to improve microglial viability and Aβ clearance in vitro. The spatial memory of transgenics was in general poorer than in wildtypes and at P360 worse in females irrespective of their genotype. This difference was accompanied by a slightly diminished dendritic complexity in females. While all the above-named sex-differences emerged after the onset of Aβ pathology, kallikrein-8 (KLK8) protease levels were, as an exception, higher in female than in male brains very early when virtually no plaques were detectable. In a second step, we quantified cerebral KLK8 levels in AD patients and healthy controls, and could ascertain, similar to mice, higher KLK8 levels not only in AD-affected but also in healthy brains of women. Accordingly, we could demonstrate that estradiol but not testosterone induces KLK8 synthesis in neuronal and microglial cells. In conclusion, multiple features of AD are more pronounced in females. Here, we show for the first time that this sex-specific difference may be meditated by estrogen-induced KLK8 overproduction long before AD pathology emerges. © 2018 International Society of Neuropathology.

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