Neuroinflammation mediates synergy between cerebral ischemia and amyloid-β to cause synaptic depression.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Origlia et al. Alzheimer's disease (AD) is the most common cause of dementia, and autopsy series suggest that cerebrovascular disease is a highly prevalent contributor. Risk factors for the development of AD tend to be related to vascular disease, including dys-lipidemia, diabetes, hypertension, and ar-teriosclerosis of blood vessels large and small, all of which impair circulation and microcirculation, and may lead to cere-bral ischemia. In support of a link between ischemia and amyloid pathology, a recent clinical neuroimaging study found that disease of the small cerebral vessels preceded the deposition of amyloid-␤ (Grimmer et al., 2012). For this reason, the mechanisms by which ischemia exacerbates the progression of AD are of interest, and animal models that include a combination of ischemia and elevated amyloid-␤ may be useful in understanding the molecular events that contribute to the progression of human AD. In their paper, Origlia and colleagues (2014) used electrophysiological recordings from mouse entorhinal cortical slices to demonstrate that oxygen and glucose deprivation (OGD) depressed synaptic transmission, and that this effect was po-tentiated by the addition of amyloid-␤. The synergy between amyloid and OGD was confirmed using a transgenic mouse model in which expression of humanized amyloid precursor protein (hmAPP) caused overproduction of amyloid-␤. In these animals, OGD increased amyloid-␤ production and an amyloid-␤-lowering ␥-secretase inhibitor ameliorated synap-tic depression in cortical slices following OGD. Thus, consistent with previous studies , it was demonstrated that amyloid-␤ could exacerbate postischemic neuronal dysfunction. In their previous work, Origlia and colleagues found that amyloid-␤ activation of the receptor for advanced glyca-tion endproducts (RAGE) induced IL-1␤ release in cortical slices (Origlia et al., 2010). Therefore in the present study, they examined RAGE and IL-1␤ as potential mediators of the deleterious syn-ergy between ischemia and amyloid-␤. They showed that a RAGE inhibitor, or microglial-specific genetic inactivation of RAGE, protected against deficits in synap-tic function elicited by OGD in the presence of amyloid-␤. They demonstrated that OGD elevated IL-1␤ and that blocking the IL-1 receptor rescued synaptic function otherwise impaired by OGD, implicating IL-1␤ as a mediator of the OGD effect on neuronal dysfunction. Collectively , …