Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid-beta (A beta) disease pathologies. Mice overexpressing both A beta and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of A beta accumulation in the brain and selectively increased the production of soluble A beta(42). PGI2 damaged the microvasculature through alterations in vascular length and branching; A beta expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.

Automated summary

Alzheimer's disease is the most common form of dementia in aged populations, and chronic neuroinflammation accelerates the neurodegenerative pathologies. The role of prostacyclin in the brain is poorly understood. A study found that upregulated prostacyclin expression worsens Aβ disease pathologies and impairs learning, memory, and behavior in a mouse model of AD.