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

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, we hypothesize 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 h 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 of 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.

Identification of Common Genes and Screening of Therapeutic Agents for Major Depressive Disorder and Alzheimer's Disease through Integrated Bioinformatics Approach

“…Hormone replacement therapy has been adopted widely in the treatment of AD. Medroxyprogesterone Acetate, a progestin, can facilitate changes in circulating levels of matrix metalloproteinases (MMPs), and dysregulation of MMPs is associated with the pathological mechanisms of AD (Porter et al, 2020). However, whether it can be utilized in the treatment of MDD and AD is still controversial.…”

The Role of Extracellular Matrix in Human Neurodegenerative Diseases

“…Hyperoxygenation treatment upregulates MMP-2, MMP-9 and tPA expression which reduces β-amyloid accumulation and rescues cognitive impairment in APP/PS1 transgenic mice [ 241 ]. Female hormones emerged as effective triggers: estrogen activates MMP-2 and MMP-9 to increase beta amyloid degradation mediated through its ERα receptor subtype—at least in SH-SY5Y human neuroblastoma cells [ 242 ]-and Medroxyprogesterone Acetatea, a progestogen used in hormonal contraception suppresses amyloid-beta degradation in an MMP-9-dependent manner in vitro, and potentially compromises the clearance of β-amyloid in vivo [ 243 ]. Androgens, like dihydrotestosterone, enhance the expression of CD147, an extracellular matrix metalloproteinase inducer, which blocks MMP-2 production, thereby increasing β-amyloid level [ 244 ].…”

Progestogen-Mediated Neuroprotection in Central Nervous System Disorders

“…One hypothesis for this divergence could be attributed to BDNF gene expression and protein levels, which can be positively modulated by progesterone, while MPA did not present this profile, in cortical organotypic explants [59]. Finally, MPA treatment has also been demonstrated to impair Aβ proteolytic degradation in rat glial cells by reducing metalloproteinase 9 expression, suggesting that it may hamper Aβ degradation in vivo [60]. This growing evidence suggests the neuroprotective and cognitive effects depend largely on the type of progestin.…”