The Interplay of Progestins, Matrix Metalloproteinases, and the Aging Brain

Progestins are synthetic hormones that are designed to mimic the biological actions of progesterone. They, however, possess other pharmacological actions and properties, in addition to their progestational activities. Medroxyprogesterone Acetate (MPA) is a progestin used globally in the hormonal contraceptive, Depo Provera®, by women in their reproductive prime and is a major compound found in hormone therapy (HT) formulations used by menopausal women. MPA is used by approximately 1 in 5 adolescents and adult women in the United States who are sexually active. Globally, nearly 48 million women utilize injectable contraceptives to prevent pregnancy, with most users utilizing MPA as their hormone of choice. Despite the extensive use of hormonal methods as either contraception or menopausal HT, there is very little known about the potential effects of these compounds on the cellular processes of the brain. Additionally, 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. Furthermore, 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. The key objective for my dissertation work was to investigate the effects of acute and chronic administration of MPA on MMP-9 production and secretion, as well as AD-related pathology, by utilizing hormonal modulation of Aβ-degrading enzymes. Two sets of studies were designed to begin addressing some of the knowledge gaps associated with MPA and its potential effects on the brain. The hypothesis of these studies was that MPA alters the levels of MMP-9 secretion and enzymatic activity, in turn, negatively impacting the degradation of Aβ and cognitive function. The first set of studies examined the outcomes of MPA on MMP-9 secretory, proteolytic, and Aβ-degrading activities. 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. The second set of studies was an in vivo assessment, evaluating the effects of chronic administration of exogenous progestins on cognitive function and MMP-9 expression. Our findings suggest that long-term, subcutaneous administration of MPA negatively impacts cognitive function, specifically memory consolidation, in wild-type (WT) mice, and enhances cognitive function, in a triple transgenic mouse model of AD (3xTg-AD), but causes a net increase MMP-9 expression in both mouse models. Collectively, these two studies demonstrated that MPA’s actions on the brain need to be further investigated and more inclusive of non-menopausal and AD models. MPA elicits a differential effect in WT and AD animals, however, increases cortical MMP-9 expression in both phenotypes. Overall, these findings suggest that MPA has the potential to elicit differential effects on women in their reproductive prime and women with predispositions for AD and should encourage more elaborate investigations of its effects

Genetic mutations in pyoderma gangrenosum, hidradenitis suppurativa, and associated autoinflammatory syndromes: Insights into pathogenic mechanisms and shared pathways

Pyoderma gangrenosum (PG), hidradenitis suppurativa (HS), and the associated autoinflammatory syndromes, including pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome, and pyogenic arthritis, pyoderma gangrenosum, acne, and suppurative hidradenitis (PAPASH) syndrome are dermatological conditions characterized by chronic inflammation and tissue damage. Recent advances in genetic research have identified specific mutations associated with these disorders, shedding light on their underlying pathogenic mechanisms. This review aims to summarize the current knowledge of identified mutations and presumed pathophysiology in PG, HS, and the associated autoinflammatory syndromes

Genetics and Etiology of Down Syndrome

This book provides a concise yet comprehensive source of current information on Down syndrome. Research workers, scientists, medical graduates and paediatricians will find it an excellent source for reference and review. This book has been divided into four sections, beginning with the Genetics and Etiology and ending with Prenatal Diagnosis and Screening. Inside, you will find state-of-the-art information on: 1. Genetics and Etiology 2. Down syndrome Model 3. Neurologic, Urologic, Dental & Allergic disorders 4. Prenatal Diagnosis and Screening Whilst aimed primarily at research workers on Down syndrome, we hope that the appeal of this book will extend beyond the narrow confines of academic interest and be of interest to a wider audience, especially parents and relatives of Down syndrome patients

Radiopharmaceuticals for PET imaging of neuroinflammation - Les radiopharmaceutiques pour l’imagerie TEP de la neuroinflammation

Abstract Recently, accumulating evidence has revealed that neuroinflammation appears to be the cornerstone of many neurological diseases including stroke, multiple sclerosis, Alzheimer's disease or Parkinson's disease. Neuroinflammation causes neuronal damages by activation of numerous cells and molecular mediators in diseases involving the inflammatory process. In this article, we focus on noninvasive molecular imaging of radioligands that target inflammatory cells and molecules involved in neuroinflammation. PET is in fact one of the most promising imaging techniques to visualize and quantify neuroinflammation in vivo. We have also summarized the potential neuroinflammation imaging targets and corresponding PET radioligands. Résumé Des données scientifiques récentes et de plus en plus nombreuses ont mis en évidence le rôle central joué par le processus de neuroinflammation dans la physiopathologie de nombreuses maladies neurologiques, telles que l’accident vasculaire cérébral, la sclérose en plaques, la maladie d’Alzheimer ou encore la maladie de Parkinson. Dans ces maladies impliquant le processus inflammatoire, la neuro-inflammation cause en effet des dommages neuronaux par activation de nombreuses cellules et médiateurs moléculaires. L’imagerie par tomographie par émission de positons (TEP) apparaît comme une approche prometteuse pour visualiser et quantifier in vivo la neuro-inflammation de façon non invasive, grâce en particulier au développement de radioligands ciblant spécifiquement diverses molécules impliquées dans cette réaction inflammatoire cérébrale. Dans cette revue sont présentés les cibles moléculaires potentielles pour l’imagerie TEP de la neuro-inflammation ainsi que les médicaments radiopharmaceutiques correspondants

Characterization of proteinase activation peptides and their potential as diagnostic markers of disease

Prostate cancer is the second leading cause of cancer death in men. While prostate specific antigen (PSA) is currently the best biomarker available, its use has many limitations. This study investigates the biosynthesis, secretion and activation of PSA. PSA is secreted as a pro enzyme containing a seven amino acid activation peptide (APLILSR). Because APLILSR is removed extracellularly in vivo, the hypothesis was tested that it may be detected in the blood or urine. Our data indicates that APLILSR is filtered from the bloodstream by the kidney, and is detectable in the urine of patients with prostate cancer, but not controls. Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease of unknown etiology. Matrix metalloproteinases (MMPs) are a family of proteinases that regulate extracellular matrix turnover and are believed to contribute to IPF. For this reason, the hypothesis that levels of MMP activation peptides will increase in patients with IPF was tested. To test these hypotheses, urine from mice were collected and an ELISA was used to quantify MMP activation peptides. These experiments show that the activation peptides of MMP-2, MMP-7, MMP-8 and MMP-9 are increased in mice with pulmonary fibrosis compared to control mice. The data also showed that that the activation peptides of MMP-2, MMP-7, and MMP-9 are increased in the urine of human patients with IPF compared to healthy controls. These data suggest that urine detection of MMP activation peptides is feasible and correlates with disease. Because urinary detection of the activation peptides of proteinases are indicative of proteinase activation in vivo, the new hypothesis that the accurate measurement of proteinase activation peptides will be relevant clinically arises, and that such measurements may aid in the diagnosis of disease and serve as a marker for following disease progression

Identification of Novel Genetic Biomarkers Linked to the Prodromal Stage of Parkinson’s Disease (PD) Patients

Background and Objective: The early diagnosis of neurodegenerative diseases, such as Parkinson\u27s disease (PD), is particularly challenging because symptoms appear only after significant neuronal damage has already occurred. This study is utilizing variant call format (VCF) analysis to identify genetic variants and novel genes that could serve as early prognostic markers for prodromal PD. Materials and Methods: Data were sourced from the Parkinson\u27s Progression Markers Initiative (PPMI), focusing on prodromal patients with gVCF data from the 2021 cohort. The study included 304 participants, comprising 100 healthy controls, 146 individuals with prodromal genetic indicators, 21 individuals with prodromal hyposmia, and 37 individuals with prodromal REM sleep behavior disorder (RBD). A specialized pipeline was developed to process the gVCF samples for variant annotation, as well as pathway and disease association analysis. Results: The analysis of prodromal subgroups revealed novel variant percentages: 1.0% in genetic males, 1.2% in genetic females, 0.6% in hyposmia males, 0.3% in hyposmia females, 0.5% in RBD males, and 0.4% in RBD females. Notably, 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300, and PPP6R2) previously identified in PD patients were also detected in the prodromal stage. Conclusion: Genetic biomarkers are playing a vital role in the early detection of Parkinson\u27s disease and its prodromal phase. The identification of these novel PD genes in prodromal patients highlights the potential for gene biomarkers to enable early diagnosis, beyond relying only on phenotypic traits

Pathophysiology of age-related diseases

A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy on 7-8 April 2009. Three lectures from that Symposium by G. Campisi, L. Ginaldi and F. Licastro are here summarized. Ageing is a complex process which negatively impacts on the development of various bodily systems and its ability to function. A long life in a healthy, vigorous, youthful body has always been one of humanity's greatest dreams. Thus, a better understanding of the pathophysiology of age-related diseases is urgently required to improve our understanding of maintaining good health in the elderly and to program possible therapeutic intervention