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Effects of Prostacyclin Signaling on Alzheimer’s Disease Associated Pathologies
Author(s) -
Womack Tasha,
Eriksen Jason L.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05459
Subject(s) - prostacyclin , neuroinflammation , downregulation and upregulation , medicine , prostaglandin h2 , neuroprotection , alzheimer's disease , microvessel , amyloid precursor protein , endocrinology , pharmacology , neuroscience , biology , inflammation , thromboxane , disease , platelet , biochemistry , angiogenesis , gene
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder that is the most common cause of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies, while epidemiological and experimental evidence suggests that use of anti‐inflammatory agents may be neuroprotective. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While is well‐established that many prostaglandins can modulate the progression of neurodegenerative disorders, little is known about the role of prostacyclin (PGI2) in the brain. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened cognitive abnormalities, accelerated amyloid pathology, and damaged the neurovasculature. PGI2 overexpression selectively increased soluble amyloid‐β 42 production, total amyloid accumulation, and burden. PGI2 altered microvessel length and branching, and PGI2 expression in combination with amyloid was more detrimental than amyloid expression alone. In vitro studies demonstrated that increased prostacyclin signaling inhibited microvessel formation and selectively altered gamma secretase subunit expression. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.