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Poster Presentations P1 hindbrain (⬃ 3600 pmole/g) suggesting that the addition of A␤42 “seeded” pathology in the bigenic mice. Conclusions: Taken together, these data suggest that A␤42 functions as a seed for the initiation of amyloid deposition and more importantly the ratio of A␤42 to A␤40, rather than the total A␤ level, may determine the extent of parenchymal and vascular A␤ deposition. P1-114

PATHOLOGICAL EFFECTS OF CLAC IN THE BRAINS OF APP/CLAC-P DOUBLE TRANSGENIC MICE

Tadafumi Hashimoto1, Daisuke Fujii1, Yuko Matsuo1, Yusuke Matsuura1, David Westaway2, Takeshi Iwatsubo1. 1University of Tokyo, Tokyo, Japan; 2University of Toronto, Toronto, ON, Canada. Contact e-mail: [email protected] Massive deposition of senile plaques (SP) in neocortices and hippocampus is the hallmark pathological lesion in Alzheimer’s disease (AD). SP are composed of amyloid fibrils formed by amyloid beta peptide (A␤). We have identified CLAC (collagenous Alzheimer amyloid plaque component) in amyloid fractions of cortices from patients with AD. CLAC co-deposits with A␤ in SP amyloid, especially in primitive-type SP in AD brains, whereas amyloid cores, vascular amyloid deposits or diffuse type plaques are CLAC-negative. We also reported that recombinant CLAC binds to fibrillized, but not soluble form of A␤ and that recombinant CLAC inhibits the elongation phase of ␤-amyloid fibril formation in vitro. To elucidate the pathological effects of CLAC in vivo, we generated transgenic (TG) mice overexpressing CLAC-P (CLAC precursor protein) in neurons under the control of Thy1.2 promoter. In the brains of CLAC-P TG mice, CLAC-P was expressed in neurons and extracellular deposits comprised of CLAC (i.e., extracellular fragment of CLAC-P) were observed in the neocortical neuropil. We next crossed CLAC-P TG mice with APP TG mice (i.e., J20 and TgCRND8). In the neocortices and hippocampus of the double TG mice, ␤-amyloid plaques were strongly positive for CLAC, whereas vascular amyloid deposits. In 12-month-old double TG mice, diffuse-type plaques and huge cored plaques were markedly decreased compared to the APP TG mice, whereas compact or multi-cored plaques of medium size were predominant. The amyloid burden (i.e., percent A␤-positive area) in the brains of double TG mice were reduced by ⬃30% (TgCRND8) or ⬃50% (J20) compared to those in the littermate APP TG mice, although the levels of SDS-insoluble A␤ quantitated by ELISA, as well as the protein expression of APP, were similar between APP TG and double TG mice. These observations suggest that the binding of CLAC to A␤ may modify the process of ␤-amyloid deposition. P1-115

CHARACTERIZATION OF PS1/APP MICE DEFICIENT FOR THE APOE RECEPTOR SORLA/ LR11

Sara E. Dodson1, Stephanie C. Carter1, Thomas Willnow2, Allan I. Levey1, James J. Lah1. 1Emory University, Atlanta, GA, USA; 2 Max Delbruck Center for Molecular Medicine, Berlin, Germany. Contact e-mail: [email protected] Background: The ApoE receptor sorLA/LR11 has been implicated in the pathobiology of Alzheimer’s disease (AD). Our initial studies established that sorLA expression is reduced in vulnerable regions of AD brain. More recently, we and others have provided evidence suggesting a role for sorLA in the processing of the amyloid precursor protein (APP). Overexpression of sorLA in vitro reduces levels of secreted beta-amyloid (A␤), a metabolite of APP that is prone to oligomerization and fibrillization in AD and believed to play a primary role in neurodegeneration. Objective(s): In the current study, we describe features of PS1/APP transgenic mice deficient in sorLA expression, which are being examined to determine whether the absence of sorLA can influence APP processing and amyloidosis in vivo. Methods: In order to recapitulate sorLA loss within an AD animal model, PS1/APP mice were crossed with sorLA knock-out mice. Plaque density and measures of soluble and insoluble A␤40 and A␤42 are in progress to

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evaluate amyloidosis in PS1/APP/LR11⫹/⫹ and PS1/APP/LR11-/- mice at various time points. Immunohistochemistry and western blotting will also be employed to examine expression levels and intracellular localization of APP and various APP metabolites. Results: PS1/APP mice crossed with sorLA knock-out mice do not express measurable levels of sorLA protein. Amyloid measures in 12 month-old mice revealed a trend towards increased amyloidosis in cortex and hippocampus of PS1/APP/LR11-/mice compared to PS1/APP/LR11⫹/⫹ littermates. Additional cohorts of younger and older mice will also be evaluated for amyloid accumulation and APP expression patterns. Conclusions: In vitro studies suggest that increased sorLA expression protects from the amyloidogenic processing of APP, and our preliminary results indicate that loss of sorLA in vivo may exacerbate amyloid accumulation in brain. SorLA/LR11 may prove to be an important, novel therapeutic target in Alzheimer’s disease. P1-116

IN VIVO IMAGING OF THE CHANGES IN MICROGLIA DYNAMICS AND MORPHOLOGY IN RELATION TO AMYLOID FORMATION

Tristan Bolmont1, Florent Haiss1, Daniel Eicke1, Rebecca Radde1, Shinichi Kohsaka2, Mathias Jucker1, Mike E. Calhoun1. 1Hertie Institute for Clinical Brain Research, Tu¨bingen, Germany; 2Department of Neurochemistry, Tokyo, Japan. Contact e-mail: [email protected] Background: Alzheimer’s disease involves glial inflammation associated with amyloid plaques. Although the morphological characteristics of microglia surrounding amyloid have been well studied, little is known about the initial dynamics and ongoing activation. Objective(s): To characterize the changes in microglial dynamics and morphology in relation to plaque development over time. Methods: Chronic intra-cranial imaging and 4D morphological analysis of microglia and amyloid in triple transgenic mice (Iba1-GFP, APPSwe, PSL166P21) and control mice (Iba1-GFP). Results: Similar to a previous report (Nimmerjahn et al., 2005), microglia in control mice rapidly surveyed their environment, sending processes extending in many directions symmetrically from their cell, at an average rate of 0.9 ␮m/min, with extension and retraction at equivalent rates. Rapid plaque formation in triple transgenic mice produced a microglial reaction, indicated by a movement of nearby microglial processes to the site of injury. Processes extended rapidly from the cell soma to contact amyloid within several hours, such that the surface area of all plaques was completely covered by microglial processes. Approximately half of the adjacent microglia (within 50␮m) subsequently migrated such that their soma was immediately adjacent to the plaque periphery over a period of 24-48 hours, whereas the soma of the other half remained distant (10-50␮m) from the plaque periphery while their processes nevertheless, maintained a constant connection to the amyloid surface. Subsequently, microglia directly adjacent to the amyloid surface adopted a macrophagic morphology, and those near plaques (⬍50␮m) became significantly polarized. This particular morphology of plaque-associated microglia left formerly-surveyed areas of the neuropil without detectable microglial coverage. Speed of microglial process movement was also altered by amyloid, with microglia adjacent to plaques exhibiting a significant decrease (14%; p⬍0.001) in speed compared to the control mice. Conclusions: We compared microglia morphology and dynamics in control mice to plaque-bearing triple transgenic mice and show the time-course of various alterations in relation to amyloid. P1-117

KINETICS OF TAU SUPPRESSION IN THE RTG4510 INDUCIBLE MODEL OF TAUOPATHY

Jada Lewis, Cindy Zehr, Joshua Knight, Dennis W. Dickson, Mike Hutton, Eileen McGowan. Mayo Clinic College of Medicine, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: The rTg4510 mouse model of tauopathy expresses inducible mutant P301L human tau in the forebrain at 15X endogenous levels. These mice develop pre-tangle pathology in the cortex and hippocampus at 2.5M and mature neurofibrillary tangle pathology at 4-5.5M of age. Significant neuronal loss is apparent from 5.5M of age and cognitive impairment can