Prostaglandin may block protective microglial cells in Alzheimer disease, a study shows. This work could form the basis for future therapies.
In Alzheimer disease, prostaglandin may block protective cells.
Prostaglandin may block protective microglial cells in Alzheimer disease (AD) animal models, specifically through signaling via its receptor, EP2, researchers at Stanford University, Stanford, Calif, and at the Cajal Institute in Madrid found. The study was published on December 8, 2014, in the Journal of Clinical Investigation.1
Microglia are essentially the immune system of the CNS, an important role because the brain and spinal cord normally are protected from conventional immune responses by the blood-brain barrier. Microglia can remove pathological proteins, such as beta-amyloid; produce neuroprotective trophic factors; and regulate inflammatory responses. In AD, impaired microglial function likely worsens the disease. Earlier research has shown that genes associated with AD control immune responses and also are expressed in microglia.2
Prostaglandins are lipids derived from fatty acids that act as local hormones, with target cells in their immediate vicinity. Cyclooxygenases (COX-1 and COX-2) can regulate their levels. Other studies have demonstrated that NSAIDs-which inhibit COX-1 and COX-2 and prostaglandin-may halt the development of AD.3 In addition, blocking the prostaglandin receptor EP2 suppresses microglial phagocytosis of the beta-amyloid protein found in the AD brain.4 Based on this information and other supporting studies, the researchers sought to examine the link between prostaglandin signaling, the EP2 receptor, and microglial function in mouse models of AD.
Led by Jenny U. Johansson, PhD, a scientist at the Department of Neurology and Neurological Sciences, Stanford University School of Medicine, the investigators used both in vitro and in vivo tests to examine microglial responses to beta-amyloid (also called AÎ²42).
The researchers first exposed peritoneal macrophages to beta-amyloid proteins and observed increased mRNA expression of the EP2 receptor in aged but not young cells. The EP2 agonist butaprost further enhanced EP2 gene expression.
In mice with the EP2 gene deleted or with EP2 signaling inhibited, beneficial microglial responses to beta-amyloid stimulation were actually enhanced. Positive effects of blocking EP2 included improvements in the clearance of the pathological beta-amyloid protein and increased production of the neuroprotective factor insulin-like growth factor-1.
Inhibiting microglial EP2 signaling in mice that were given intraventricular beta-amyloid improved their performance in a memory task and decreased brain inflammatory responses. Brain inflammation can impair cognitive function. Deleting the EP2 gene in an established transgenic mouse model of AD (APP-PS1 mice) also improved performance in a spatial memory task.
Dr Johansson told Neurology Times, “This may be a step in the further development of anti-inflammatory treatment in Alzheimer’s disease. In particular, epidemiological studies have shown promising results with the use of non-steroidal anti-inflammatory drugs as prevention of Alzheimer’s. The use of these COX-inhibitors, however, broadly blocks prostaglandin production and can give adverse side effects. We believe that specifically blocking the EP2 receptor in microglia represents a targeted approach that would boost immune function and dampen toxic inflammation and may also circumvent these side effects.”
This work could form the basis for future therapies to treat AD, targeting EP2 signaling, although further studies in humans are naturally needed.
Dr Johansson noted, “We are hoping to move forward with our studies on EP2 but realize that it will take time before patients can benefit, as these initial results are from mice.”
• Prostaglandin may block protective microglial cells in AD.
• Signaling via the prostaglandin receptor, EP2, is responsible for the inhibition of beta-amyloid–induced microglial responses.
• Targeting the EP2 prostaglandin receptor may provide a strategy for treating patients with AD.
1. Johansson JU, Woodling NS, Wang Q, et al. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models. J Clin Invest. 2014 Dec 8. pii: 77487. doi: 10.1172/JCI77487. [Epub ahead of print]
2. Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011; 43:436-441.
3. in t’ Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med. 2001;345:1515-1521.
4. Shie FS, Montine KS, Breyer RM, Montine TJ. Microglial EP2 as a new target to increase amyloid beta phagocytosis and decrease amyloid beta-induced damage to neurons. Brain Pathol. 2005;15:134-138.