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Human Amyloid Precursor Protein (human + amyloid_precursor_protein)
Selected AbstractsTransplanted astrocytes internalize deposited ,-amyloid peptides in a transgenic mouse model of Alzheimer's diseaseGLIA, Issue 2 2008Rea Pihlaja Abstract Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. The neuropathological hallmarks include extracellular senile plaques consisting of deposited ,-amyloid (A,) peptides and intraneuronal neurofibrillary tangles. Neuroinflammation and activation of astrocytes are also well-established features of AD neuropathology; however, the relationships between astrocytes and A, deposition remain unclear. Previous studies have shown that adult mouse astrocytes internalize and degrade A, deposits in brain sections prepared from human amyloid precursor protein (APP) transgenic mice. In the present study, we demonstrate that cultured adult, but not neonatal mouse astrocytes, respond morphologically and degrade A, deposits present in human AD brain. We also transplanted astrocytes isolated from enhanced green fluorescent protein expressing adult and neonatal mice into the hippocampi of human A, plaque-bearing transgenic APPSwe+PS1dE9 (APdE9) mice and their wild-type littermates and followed the migration and localization of these astrocytes by confocal microscopy upto 7 days after transplantation. Posttransplantation the astrocytes localized as aggregates or thin strings of many cells within the hippocampi of APdE9 and wild-type mice and showed limited migration from the injection site. Interestingly, most of the transplanted astrocytes were found near A, deposits in the hippocampi of APdE9 mice. In contrast to findings in ex vivo degradation assay, confocal microscopy revealed that both adult and neonatal transplanted astrocytes internalized human A, immunoreactive material in vivo. These results support the role of astrocytes as active A, clearing cells in the CNS that may have important implications for future development of therapeutic strategies for AD. © 2007 Wiley-Liss, Inc. [source] Neuronal cholesterol esterification by ACAT1 in Alzheimer's diseaseIUBMB LIFE, Issue 4 2010Ta-Yuan Chang Abstract Cholesterol has been implicated in various neurodegenerative diseases. Here we review the connection between cholesterol and Alzheimer's disease (AD), focusing on a recent study that links neuronal cholesterol esterification with biosynthesis of 24(S)-hydroxycholesterol and the fate of human amyloid precursor protein in a mouse model of AD. We also briefly evaluate the potential of ACAT1 as a drug target for AD. © 2010 IUBMB IUBMB Life, 62(4): 261,267, 2010 [source] Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque depositionPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2007Frank Gillardon Dr. Abstract Synaptic dysfunction is an early event in Alzheimer's disease patients and has also been detected in transgenic mouse models. In the present study, we analyzed proteomic changes in synaptosomal fractions from Tg2576 mice that overexpress mutant human amyloid precursor protein (K670N, M671L) and from their nontransgenic littermates. Cortical and hippocampal tissue was microdissected at the onset of cognitive impairment, but before deposition of amyloid plaques. Crude synaptosomal fractions were prepared by differential centrifugation, proteins were separated by 2-D DIGE and identified by MS/MS. Significant alterations were detected in mitochondrial heat shock protein 70 pointing to a mitochondrial stress response. Subsequently, synaptosomal versus nonsynaptic mitochondria were purified from Tg2576 mice brains by density gradient centrifugation. Mitochondrial proteins were separated by IEF or Blue-native gel electrophoresis in the first dimension and SDS-PAGE in the second dimension. Numerous changes in the protein subunit composition of the respiratory chain complexes I and III were identified. Levels of corresponding mRNAs remain unchanged as shown by Affymetrix oligonucleotide array analysis. Functional examination revealed impaired state 3 respiration and uncoupled respiration in brain mitochondria from young Tg2576 mice. By immunoblotting, amyloid-beta oligomers were detected in synaptosomal fractions from Tg2576 mice and reduced glucose metabolism was observed in Tg2576 mice brains by [14C]-2-deoxyglucose infusion. Taken together, we demonstrate alterations in the mitochondrial proteome and function that occur in Tg2576 mice brains before amyloid plaque deposition suggesting that mitochondria are early targets of amyloid-beta aggregates. [source] Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-, oligomersANNALS OF NEUROLOGY, Issue 2 2010Sam Gandy MD Objective Recent evidence suggests that high molecular weight soluble oligomeric A, (oA,) assemblies (also known as A,-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in Alzheimer disease (AD). To date, most in vivo studies of oA,/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of A,-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oA,/ADDLs generated in situ from the physiological processing of human amyloid precursor protein (APP) and presenitin1 (PS1) transgenes. Methods We produced and histologically characterized single transgenic mice overexpressing APPE693Q or APPE693Q X PS1,E9 bigenic mice. APPE693Q mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for A,total, A,40, A,42, and oA,/ADDLs by enzyme-linked immunosorbent assay (ELISA) and were also histologically examined. Based on results from the oA,/ADDL ELISA, we assigned individual APPE693Q mice to either an undetectable oA,/ADDLs group or a readily detectable oA,/ADDLs group. A days to criterion (DTC) analysis was used to determine delays in acquisition of the MWM task. Results Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/A,, although only APPE693Q X PS1,9 bigenic mice developed amyloid plaques. The APPE693Q mice did not develop amyloid plaques at any age studied, up to 30 months. APPE693Q mice were tested for spatial learning and memory, and only 12-month-old APPE693Q mice with readily detectable oA,/ADDLs displayed a significant delay in acquisition of the MWM task when compared to nontransgenic littermates. Interpretation These data suggest that cerebral oA,/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human A, assemblies. ANN NEUROL 2010 [source] | ||||||||||