Recent studies have found that women are bearing a disproportionate amount of the Alzheimer?s disease this disease it produces less progesterone and estrogens and there is a correlation between early onset of menopause (and hence a decline in sex steroid levels) with increased Alzheimer?s disease susceptibility. Steroid hormones regulate physiology of many tissues, among which is the choroid plexus- an epithelial tissue responsible for secretion of cerebrospinal fluid (CSF), the fluid that protects the brain, provides it with nutrients and hormones, and removes waste products. With aging, the choroid plexus fails to maintain adequate CSF production and turnover and this may contribute to the onset of cognitive decline and development of the Alzheimer?s disease the molecular mechanism of its action remains burden: at the age of 65, women have a 1 in 5 chance of developing , compared to a 1 in 11 chance for men. As the female body ages, . Steroid hormone progesterone is known to regulate fluid homeostasis in the choroid plexus, however, elusive. We recently discovered that while choroid plexus does not express any canonical nuclear-localized progesterone receptors, it does highly express the unconventional membrane progesterone receptor ?/? hydrolase domain?containing protein 2 (ABHD2). Global knockout of Abhd2 produces mice with smaller brain ventricles and narrower choroid plexus capillaries. Our preliminary data indicate the steroid signaling in the choroid plexus , and since steroid levels decline with age, turnover of CSF production may be altered by a narrower choroid plexus capillary network due to decreased steroid content. we seek to study (1) the physiological role of ABHD2 and its downstream effectors in the choroid plexus of the aging brain by generating conditional knockouts of Abhd2 and other targeted genes specifically in the choroid plexus; and (2) to explore the mechanism between CSF turnover with age and the role steroid hormones play in it. Our team has matching expertise in acute tissue-specific gene knockdown in the aging mouse brain and biophysical characterization of the choroid plexus function. The outcome of this research will help to establish physiological role of ABHD2 in the choroid plexus and its alteration during aging and Alzheimer?s disease. Additionally, this work will reveal novel could be linked to CSF turnover Here molecular pathways that may explain gender- differences in steroid regulation of CSF production and why Alzheimer?s disease affects women at a higher rate. Finally, data obtained from this project will form the basis for a joint R01 grant application, which will allow us to expand our teams? research on steroid regulation of the brain function and its role in Alzheimer?s disease.

Public Health Relevance

The turnover and clearance of the cerebrospinal fluid plays an important role in aging, but our understanding of the molecular mechanism of this regulation is severely limited. Here we describe the physiological function of a novel progesterone-regulated enzyme that controls the calcification and diameters of the choroid plexus capillary and contributes to the aging of this tissue. The proposed research may explain why certain neurogenerative diseases affects women at a higher rate.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Mackiewicz, Miroslaw
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University of California Berkeley
Schools of Arts and Sciences
United States
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