Cannabinoid CB2 Receptors in a Mouse Model of A beta Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation

In Alzheimer\u27s disease (AD), one of the early responses to A beta amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of A beta-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1 Delta E9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1 Delta E9 mice were used in small animal PET with a CB2-targeting radiotracer, [C-11]A836339. These studies revealed increased binding of [C-11]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with A beta plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that A beta amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed

Protecting America Through Better Civic Education

CHDS State/LocalHow does civic education affect homeland security? A civic education curriculum that provides for the foundations of our youths individual and collective identity may significantly contribute to the preservation of our democracy and enhance homeland security. Through a civic education, students can enhance their grasp of the concepts of our American representative democracy and learn the tenets of good citizenship, critical thinking, and the ability to self-govern. Presidential Directive Number Eight (8) clearly indicates the need for national preparedness using a whole of nation approach. The plan requires robust citizen engagement. To have an informed engaged citizenry and for a democracy to thrive, the populace must be educated. But there is no guidance or mention of the education of American youth or how such education may play a role in achieving the goals of national preparedness. The National Assessment of Educational Progress (NAEP) reported in 2010 that only 27 percent of the nations fourth-grade students were proficient in civics. Only 22 percent and 24 percent of eighth-grade and twelfth-grade students, respectively, were proficient in the area. Civic education must provide youth with a personal and collective identity.http://archive.org/details/protectingameric1094537698Captain, Amtrak Police Departmen

Use of positron emission tomography to study AT1 receptor regulation in vivo

Increased sodium intake and enhanced sodium sensitivity are implicated in the pathogenesis of hypertension and in the control of a major regulator of BP, the type 1 angiotensin receptor (AT(1) receptor). An in vivo technique to study changes of renal AT(1) receptors by dietary sodium was developed that uses positron emission tomography (PET). PET revealed that renal cortical AT(1) receptor binding was increased in sodium-loaded compared with sodium-deprived dogs, which correlated with ex vivo estimations of AT(1) receptor numbers. Plasma renin activity, angiotensin II, and aldosterone were inversely related to changes in AT(1) receptor binding. These results demonstrate, for the first time in vivo, that the renal AT(1) receptor is inversely related to the activity of the renin angiotensin system, which may provide a compensatory mechanism to prevent inappropriate fluctuations in arterial BP. The ability to measure AT(1) receptor binding in vivo has potential significance for clinical studies of AT(1) receptors, because PET is a noninvasive imaging technique that is readily applicable in humans