Statistical significance was determined using Students [14], we categorized the plaques according to their size: 1) small, 400m2; 2) medium, 401m2 – 700m2; 3) large, 700m2. diminished in the later stages of plaque evolution ( 150 days). These findings support the view that microglia serve to restrict the growth of senile Acolbifene (EM 652, SCH57068) plaques, and Acolbifene (EM 652, SCH57068) do so in a way that minimizes local inflammatory damage to other components of the brain. studies showed that activated microglia migrate toward newly developing A plaques within 1-2 days of the appearance of the aggregated A, and also that the microglia are attracted to more mature A deposits. After their recruitment to the plaque, the cells appeared to restrict plaque growth and were capable of reducing plaque size; however, the existing A deposits were not removed [3, 14]. Moreover, in an investigation of the dynamic interaction of microglia and plaques, Bolmont and colleagues [14] recognized plaques that were more prone to increase in volume over time, possibly owing to a reduced presence of microglia. Furthermore, an upper limit of the number of microglia associated with plaques, independent of plaque size, may indicate diminished migratory behavior or restricted infiltration of monocytes from the periphery. These findings indicate an important contribution of microglia to the evolution of A deposits, and thus could provide insights into the mechanisms by which A immunotherapy [15] affects these lesions in the brains of AD patients. Both active and passive anti-A immunization approaches have entered human clinical trials [16]. In preclinical studies of transgenic mice, systemic administration of the mouse monoclonal antibody m266 not only decreased plaque formation [17] but also rapidly improved behavioral performance [18, 19]. In contrast, the initial phase 2a trial of the active immunization approach was prematurely terminated due to an apparent subacute meningoencephalitis [20]. The first post-mortem analyses revealed increased microglial activation and expression of the phagocytosis marker CD68 [21] on the microglia, apparent clearance of A plaques, and the presence of immunoreactive A within activated microglia [22, 23]. Despite these effects on plaques, none of the treated patients showed significant improvement of cognitive abilities [24]. At least with regard to the clearance of senile plaques, these data are largely consistent with A-immunization experiments in animal models [25], and further support the hypothesis that antibody-mediated microglial activation results in the phagocytosis of A and clearance of parenchymal plaques [26, 27]. Indeed, recent analyses suggest that CAA, which increases in the early stages of plaque removal, also may be eliminated by immunotherapy after an extended period of time [24]. Hence, if the power and specificity of microglia can be safely harnessed, selective microglial activation keeps promise as a means of reducing A burden in the brains of individuals with AD. To clarify the temporal and spatial human relationships between -amyloid plaques and microglia, we used an APP/PS1 transgenic mouse model of cerebral -amyloidosis [28]. With the help of a newly developed, 230nm-high-resolution, semi-automated, quantitative evaluation method including microscopy and automated computer analysis, we were able to focus on the time-course of microglial activation and -amyloid deposition in thin time increments starting with the onset of plaque deposition at day time 50. We found that microglia react strongly to early plaque formation, and that they may contribute to plaque size restriction. These results support the potential energy of antibody-mediated microglial activation for restorative interventions. METHODS Animals We investigated in an 25 day time rhythm, starting at day time 50 until day time 200 of each three to five male and female transgenic mice harboring mutant human being presenilin 1 (L166P variant) and a mutant human being -amyloid precursor protein (APPswe) on a C57Bl/6J background (APP/PS1) [28]. The mice were managed at 23-25C on Igf2 a 12h:12h light:dark cycle, with free access to rodent food and water. All procedures were conducted Acolbifene (EM 652, SCH57068) Acolbifene (EM 652, SCH57068) in accordance with animal protocols authorized by the University or college of Rostock and according to the state law of the government of Mecklenburg-Vorpommern (LALLF M-V/TSD/7221.3-2.3-004/06; LALLF M-V/TSD/7221.3-2.3-003/08). Immunohistochemistry Immunohistochemistry.