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-β (Aβ) disease pathologies. Mice overexpressing both Aβ 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 Aβ accumulation in the brain and selectively increased the production of soluble Aβ42. PGI2 damaged the microvasculature through alterations in vascular length and branching; Aβ 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

Microglia in the Alzheimer's brain: a help or a hindrance?

Alzheimer’s disease (AD), the leading cause of dementia, is a complex neurodegenerative disorder. The AD brain is characterized by the presence of Amyloid-β (Aβ) plaques, neurofibrillary tangles, and an increased inflammatory response. Microglia, the chief immune cells of the central nervous system, have been implicated in AD due to their strong association with Aβ plaques. The role of inflammation associated with microglia has been hotly contested in development of Alzheimer’s disease. A growing amount of genetic studies have implicated microglia in late-onset AD and their role in Aβ clearance. Although traditionally microglia have been considered to be either in resting or activated states, these cells are now known to exist in multiple heterogeneous populations and altered roles that appear to impact pathological states of the Alzheimer’s brain