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Cited by 17Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsNeuroinflammation and Neurodegeneration Mechanisms

Medroxyprogesterone Acetate Impairs Amyloid Beta Degradation in a Matrix Metalloproteinase-9 Dependent Manner

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Porter, Keyana N., Sarkar, Saumyendra N., Dakhlallah, Duaa A., Vannoy, Mya E., Quintana, Dominic D., Simpkins, James W.·2020·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2020.00092PMC PMC7155169
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Abstract

Despite the extensive use of hormonal methods as either contraception or menopausal hormone therapy (HT), there is very little known about the potential effects of these compounds on the cellular processes of the brain. Medroxyprogesterone Acetate (MPA) is a progestogen used globally in the hormonal contraceptive, Depo Provera, by women in their reproductive prime and is a major compound found in HT formulations used by menopausal women. MPA promotes changes in the circulating levels of matrix metalloproteinases (MMPs), such as MMP-9, in the endometrium, yet limited literature studying the effects of MPA on neurons and astroglia cells has been conducted. Additionally, the dysregulation of MMPs has been implicated in the pathology of Alzheimer’s disease (AD), where inhibiting the secretion of MMP-9 from astroglia reduces the proteolytic degradation of amyloid beta. Thus, our hypothesis is that exposure to MPA disrupts proteolytic degradation of amyloid beta through the downregulation of MMP-9 expression and subsequent secretion. To assess the effect of progestins on MMP-9 and amyloid beta, in vitro, C6 rat glial cells were exposed to MPA for 48 hours and then the enzymatic, secretory, and amyloid beta degrading capacity of MMP-9 was assessed from the conditioned culture medium. We found that MPA treatment inhibited transcription of MMP-9, which resulted in a subsequent decrease in the production and secretion of MMP-9 protein, in part through the glucocorticoid receptor. Additionally, we investigated the consequences on amyloid beta-degrading activity and found that MPA treatment decreased proteolytic degradation of amyloid beta. Our results suggest MPA suppresses amyloid beta degradation in an MMP-9-dependent manner, in vitro, and potentially compromises the clearance of amyloid beta in vivo.

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  • Stimulation of endothelial cells with Aβ or proinflammatory cytokines reduced expression of tight junction proteins Claudin-5, VE-cadherin and Occludin, thus increasing permeability.

    “Multiple in vitro experiments revealed that stimulation of endothelial cells with Aβ or proinflammatory cytokines reduced the expression of tight junction proteins like Claudin-5, VE-cadherin and Occludin, thus increased permeability.474–478”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [474]

    The Introduction discusses Aβ-induced MMP expression in neurons and astroglia and mentions a general role for MMPs in blood–brain barrier integrity; the Discussion concerns Aβ degradation by astroglia. Searches for endothelial tight-junction proteins and permeability found no passage reporting that Aβ or cytokines reduced Claudin-5, VE-cadherin, or Occludin expression in endothelial cells. (LLM, conf=0.74)

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Cited by

Sorted by citations

Authors
Porter, K. N., Sarkar, S. N., Dakhlallah, D. A., Vannoy, M. E., Quintana, D. D., & Simpkins, J. W.
Affiliations
West Virginia University (US)
Corresponding author
Simpkins, James W.
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2020-04-07
Volume
12
Pages
92-92
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2020.00092
PMC
PMC7155169
OpenAlex
W3015461897
Cited by
17
References
7
Citations by year
2026: 2 · 2023: 6 · 2022: 8 · 2021: 1
FWCI
2.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AG027956, GM104942, GM109098)
  • National Institute on Aging (P01AG027956, T32AG052375)
  • National Institute of General Medical Sciences (P20GM109098, U54GM104942)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
medroxyprogesterone acetate, MMP-9, amyloid beta degradation, progestins, hormone replacement therapy, hormonal contraception, Alzheimer's disease, glucocorticoid receptor, astrocytes, C6 glioma cells, amyloid-beta clearance, MMP-9 secretion

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