microscopic changes in the brains of triple transgenic (3xTg) mice that over-express three mutations: APPswePS1M146V, and tauP301LResults: Histo-chemical and immunohistoHisto-chemical staining combined with computerized stereology of systematically sampled sections from 3xTg mice in three age groups [8, 12, and 15 months] revealed remarkable similarities and dif-ferences relative to age-matched dtg APPswe/PS1DE9 mice. While 3xTg mice show significant age-related loss of TH+ neurons in LC, they do not show age-related loss of CA1 neurons as seen in dtg APPswe/PS1DE9 mice. The 3xTg mice have a distinctive pattern of extracellular distribution of amyloid plaques limited primarily to the subiculum of hippocampal for-mation and neocortical layer V and intracellular Aß deposition primarily in subiculum and CA1 pyramidal neurons. Furthermore, significant differ-ences were found in the degree of astrogliosis and microgliosis in dtg APPswe/PS1DE9and 3xTg mice.Conclusions:Understanding the neurobio-logical bases for these similarities and differences in AD-type neuropathol-ogy in response to the deposition of mutant Aß peptides could provide insight into neuropathology underlying cognitive impairment in AD.
P3-024 HIPPOCAMPAL SYNAPTIC PLASTICITY IN ALZHEIMER’S DISEASE: WHAT HAVE WE LEARNED SO FAR FROM TRANSGENIC MODELS?
Cristina Marchetti*1, H
elene Marie2,1
EBRI- European Brain Research Institute, Italy;2IPMC - CNRS UMR6097, Sophia-Antipolis, France.
Background:Transgenic (TG) mouse models of Alzheimer’s disease (AD) have been used for over 15 years to investigate mechanisms underlying dis-ease pathology and identify therapeutic strategies. Most TG AD mouse models, which at least partly recapitulate the phenotype of AD, are based on one or more known human mutations (identified in Familial AD) inserted in the mouse genome; with the notable exception of the anti-NGF mouse, based on the cholinergic unbalance hypothesis. It has recently emerged that impaired synaptic function, in particular in the hippocampus, is an early detectable sign of the disease, well before the advanced stage in which am-yloid plaques accumulate and general cellular apoptosis takes place. Never-theless, electrophysiological studies performed on the different TG models or on the same model by different research groups have yielded contrasting results.Methods:We analyzed all available original research papers study-ing in-vivo or in-vitro hippocampal synaptic function usstudy-ing electrophysiol-ogy from the following groups of TG mouse models: 1) single or multiple APP mutations, 2) single presinilin (PS) mutations, 3) APP3PS mutations, 4) APP3PS1X TAU mutations 5) anti-NGF expressing mice. We com-pared results on excitatory and inhibitory basic synaptic transmission ob-tained by different laboratories. We also compared results for short- and long-term synaptic plasticity.Results:We observed that the majority of pa-pers focuses and report contradicting results on excitatory and inhibitory ba-sic transmission and long-term potentiation while only a small percentage of papers evaluate inhibitory transmission and long-term depression. Our anal-ysis searched for common denominators of synaptic alterations in the vari-ous mvari-ouse models that could provide new insights into hippocampal dysfunctions underlying the memory deficits observed in these mice. We further analyzed experimental variables that could determine differences in reported results e.g. the presence of inhibitory transmission blockers and calcium concentration in the recording extracellular medium. Conclu-sions:We conclude that, in the future, in-vitro experiments should take into account the identified common denominators for further validation and carefully address experimental design for ease of comparison.
P3-025 LOWERING PERIPHERAL Aß IS SUFFICIENT TO REVERSE COGNITIVE IMPAIRMENT IN TG2576 MICE
Anelise Marti*1, Chantal Mathis2, Deepak Lala3, Ralf Lotz1,
Scott Hobson1, Larry Dillard3, Thorsten Lamla1, Martin Lenter1,
Jean-Christophe Cassel2, Cornelia Dorner-Ciossek1,1Boehringer Ingelheim
Pharma GmbH & Co. KG, Biberach, Germany;2LINC, UMR 7237
-Universite de Strasbourg - CNRS, Strasbourg, France;3Vitae
Pharmaceuticals, Inc, Fort Washington, Pennsylvania, United States.
Background:Tg2576 mice, one of the most widely used transgenic mouse model of Alzheimer’s diease, develop age-dependent memory deficits. Sev-eral therapeutical agents have been reported to reverse these cognitive def-icits either partially (donepezil, rolipram) or completely (gamma-secretase inhibitor, antibodies against Aß). The aim of this work was to establish a cor-relation between the reduction of Aß and the reversal of the cognitive im-pairment of the Tg2576 mice assessed in a spatial recognition task. Methods:We first confirmed that the anti Aß antibody m266, which mas-sively decreases plasma Aß, could reverse completely the memory impair-ment of the Tg2576 mice in this task. Inhibition of gamma-secretase and BACE, resulting in a significant reduction of brain Aß, also reversed the def-icit of the Tg2576 mice in this task. In order to determine how much central Aß lowering is needed to induce this improvement, we used different doses of a BACE inhibitor.Results:Our data show that a low dose of the BACE inhibitor reduced 60% of plasma Aß without affecting brain Aß levels but completely reversed the cognitive impairment of Tg2576 mice. Conclusions:Our results suggest that reduction of plasma Aß levels is suf-ficient to reverse the cognitive impairment in the Tg2576 mouse model of Alzheimer’s disease
P3-026 EFFECTS OF AMYLOID (1-42) PEPTIDE ON CORTICAL NEURON/GLIA CULTURES FROM PARKIN NULL MICE. ROLE OF AUTOPHAGY AND GLUTATHIONE HOMEOSTASIS
Rosa Solano*1, Maria Casarejos1, Ana Gomez1, Juan Perucho1, Justo de
Yebenes1, Maria Mena2,1
Hospital Ramon y Cajal, Madrid, Spain;2Ramon y Cajal Hospital, Madrid, Spain.
Background:The production and aggregation of amyloid beta peptides (A-beta) has been linked to the development and progression of Alzheimer’s disease (AD). A-beta 1-42 is increased in patients affected by AD, both in familial and sporadic cases. Parkin mutations impair ubiquitin-proteasome pathways and produce familial Parkinson’s disease (PD) in humans. Parkin may play a role in the processing of A-beta 1-42.Methods:Transgenic an-imals were obtained from 129SV/C57BL6 wild type (+/+) or parkin null (-/-) mice (Itier et al. 2003). Neuronal and glial cortical primary cultures were derived from littermate -/- and +/+ embryos obtained from homozy-gous colonies previously generated by heterozyhomozy-gous parkin -/+ intercross. The genotype was confirmed by PCR analysis of tail tissue and by WB anal-ysis of parkin in the cultures (Casarejos et al. 2005; Solano et al. 2008). Neu-ronal and glial cortical primary cultures were obtained at 16 days of gestation and grown in Neurobasal medium supplemented with B27, during 7 days.Results:The treatment of mixed neuron/glia cultures with A-beta 1-42, 4.4 uM, for 48 h induced significant cell death by necrosis (trypan blue) and apoptosis (TUNEL). These effects were both more pronounced in WT than in PK-KO neurons. In WT cultures the treatment with A-beta 1-42 re-duced both the total number of cells as well as the number of astrocytes, ex-pressed as the area of GFAP+ cells. However, the treatment with A-beta 1-42 increased more the percentage of microglia in PK-KO than in WT cultures. The temporal profile of activation of ERK 1/2 and AKT proteins showed a rapid increase of phospho-proteins with a maximum increase of activation 10 minute after treatment with A-beta 1-42 in PK-KO glial cells. Ptreat-ment with an inhibitor of GSH synthesis and the inhibition of autophagy, re-verted the increased resistance to A-beta of the PK-KO cultures. Conclusions:Neuron/glia PK-KO cultures are more resistant to A-beta in-duced toxicity than WT cultures. Supported by: FIS 2010/172, Laın En-tralgo NDG07/4, CAM 02/02/2006, and CIBERNed 2006/05/059 and 2010.
P3-027 TREHALOSE PROTECTS FROM AGGRAVATION
OF AMYLOID PATHOLOGY INDUCED BY ISOFLURANE ANESTHESIA IN APPswe MUTANT MICE
Juan Perucho*1, Maria Casarejos1, Ana Gomez1, Rosa Solano1, Justo de
Yebenes1, Maria Mena2,1Hospital Ramon y Cajal, Madrid, Spain;2Ramon
y Cajal University Hospital, Madrid, Spain.
