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Plaque Deposition (plaque + deposition)
Kinds of Plaque Deposition Selected AbstractsAntibodies against ,-amyloid reduce a, oligomers, glycogen synthase kinase-3, activation and , phosphorylation in vivo and in vitroJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2006Qiu-Lan Ma Abstract Although active and passive immunization against the ,-amyloid peptide (A,) of amyloid plaque-bearing transgenic mice markedly reduces amyloid plaque deposition and improves cognition, the mechanisms of neuroprotection and impact on toxic oligomer species are not understood. We demonstrate that compared to control IgG2b, passive immunization with intracerebroventricular (icv) anti-A, (1,15) antibody into the AD HuAPPsw (Tg2576) transgenic mouse model reduced specific oligomeric forms of A,, including the dodecamers that correlate with cognitive decline. Interestingly, the reduction of soluble A, oligomers, but not insoluble A,, significantly correlated with reduced , phosphorylation by glycogen synthase kinase-3, (GSK-3,), a major , kinase implicated previously in mediating A, toxicity. A conformationally-directed antibody against amyloid oligomers (larger than tetramer) also reduced A, oligomer-induced activation of GSK3, and protected human neuronal SH-SY5Y cells from A, oligomer-induced neurotoxicity, supporting a role for A, oligomers in human , kinase activation. These data suggest that antibodies that are highly specific for toxic oligomer subspecies may reduce toxicity via reduction of GSK-3,, which could be an important strategy for Alzheimer's disease (AD) therapeutics. © 2005 Wiley-Liss, Inc. [source] Preparation, physiochemical characterization, and oral immunogenicity of A,(1,12), A,(29,40), and A,(1,42) loaded PLG microparticles formulationsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2009R. Rajkannan Abstract Alzheimer's disease (AD) is caused by the deposition of ,-amyloid (A,) protein in brain. The current AD immunotherapy aims to prevent A, plaque deposition and enhance its degradation in the brain. In this work, the peptides B-cell epitope A,(1,12), T-cell epitope A,(29,40) and full-length A,(1,42) were loaded separately to the poly (D,L -lactide co-glycolide) (PLG) microparticles by using W/O/W double emulsion solvent evaporation method with entrapment efficacy of 70.46%, 60.93%, and 65.98%, respectively. The prepared A, PLG microparticles were smooth, spherical, individual, and nonporous in nature with diameters ranging from 2 to 12 µm. The cumulative in vitro release profiles of A,(1,12), A,(29,40), and A,(1,42) from PLG microparticles sustained for long periods and progressively reached to 73.89%, 69.29%, and 70.08% by week 15. In vitro degradation studies showed that the PLG microparticles maintained the surface integrity up to week 8 and eroded completely by week 16. Oral immunization of A, peptides loaded microparticles in mice elicited stronger immune response by inducing anti-A, antibodies for prolonged time (24 weeks). The physicochemical characterization and immunogenic potency of A, peptides incorporated PLG microparticles suggest that the microparticles formulation of A, can be a potential oral AD vaccine. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2027,2039, 2009 [source] Visualization of ,-amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagentsMAGNETIC RESONANCE IN MEDICINE, Issue 3 2004Sang-Pil Lee Abstract The visualization of ,-amyloid plaque deposition in brain, a key feature of Alzheimer's disease (AD), is important for the evaluation of disease progression and the efficacy of therapeutic interventions. In this study, ,-amyloid plaques in the PS/APP transgenic mouse brain, a model of human AD pathology, were detected using MR microscopy without contrast reagents. ,-Amyloid plaques were clearly visible in the cortex, thalamus, and hippocampus of fixed brains of PS/APP mice. The distribution of plaques identified by MRI was in excellent agreement with those found in the immunohistological analysis of the same brain sections. It was also demonstrated that image contrast for ,-amyloid plaques was present in freshly excised nonfixed brains. Furthermore, the detection of ,-amyloid plaques was achieved with a scan time as short as 2 hr, approaching the scan time considered reasonable for in vivo imaging. Magn Reson Med 52:538,544, 2004. © 2004 Wiley-Liss, Inc. [source] Familial British dementia (FBD): a cerebral amyloidosis with systemic amyloid depositionNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2002J. L. Holton Introduction:, FBD is an autosomal dominant disease with neuropathological similarities to Alzheimer's disease (AD) as it is characterized by amyloid angiopathy, parenchymal amyloid plaque deposition and neurofibrillary degeneration. FBD is associated with a stop codon mutation in the BRI2 gene encoding a type II transmembrane protein, BriPP. Mutation results in an extended precursor protein, ABriPP, from which a C-terminal 34 amino acid peptide (ABri) is generated by furin-like proteolytic cleavage and deposited as amyloid and preamyloid in the central nervous system. Despite the morphological parallels with AD the sequences of the amyloidogenic peptides, ABri in FBD and A, in AD, are completely different. We examined systemic tissues in FBD for ABri deposition. Materials and methods:, Immunohistochemistry using an ABri-specific antibody, Ab338, counterstained with Thioflavin S and Ab338 immuno-electron microscopy identified ABri deposits and determined whether these were amyloid or preamyloid in nature. Results:, Amyloid bearing blood vessels stained positively for ABri in myocardium, uterus, bladder, spleen, pancreas, lung and skeletal muscle. ABri was also identified in either amyloid or preamyloid conformation in the parenchyma of myocardium, adrenal, pancreas and skeletal muscle. Conclusion:, This study demonstrates that FBD is the first described cerebral amyloidosis with neurofibrillary pathology and dementia to be accompanied by systemic amyloid deposition. [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] Intraneuronal APP/A, Trafficking and Plaque Formation in ,-Amyloid Precursor Protein and Presenilin-1 Transgenic MiceBRAIN PATHOLOGY, Issue 3 2002Oliver Wirths Neuropil deposition of ,-amyloid peptides A,40 and A,42 is believed to be the key event in the neurodegenerative processes of Alzheimer's disease (AD). Since A, seems to carry a transport signal that is required for axonal sorting of its precursor ,-amyloid precursor protein (APP), we studied the intraneuronal staining profile of A, peptides in a transgenic mouse model expressing human mutant APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS-1 M146L) in neurons. Using surface plasmon resonance we analyzed the A, antibodies and defined their binding profile to APP, A,40 and A,42. Immunohistochemical staining revealed that intraneuronal A,40 and A,42 staining preceded plaque deposition, which started at 3 months of age. A, was observed in the somatodendritic and axonal compartments of many neurons. Interestingly, the striatum, which lacks transgenic APP expression harbored many plaques at 10 months of age. This is most likely due to an APP/A, transport problem and may be a model region to study APP/A, trafficking as an early pathological event. [source] REVIEW: ,-Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current StateCNS: NEUROSCIENCE AND THERAPEUTICS, Issue 5 2010Francesco Panza SUMMARY Aims: Drugs currently used for the treatment of Alzheimer's disease (AD) partially stabilize patients' symptoms without modifying disease progression. Brain accumulation of oligomeric species of ,-amyloid (A,) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating A, formation from amyloid precursor protein (APP). This article briefly reviews the profile of ,-secretase inhibitors, compounds that inhibit ,-secretase, the pivotal enzyme that generates A,, and that have reached the clinic. Discussion: Several classes of potent ,-secretase inhibitors have been designed and synthesized. Preclinical studies have indicated that these compounds are able to lower brain A, concentrations and, in some cases, reduce A, plaque deposition in transgenic mouse models of AD. The most developmentally advanced of these compounds is semagacestat, presently in Phase III clinical trials. In animals, semagacestat reduced A, levels in the plasma, cerebrospinal fluid (CSF), and the brain. However, studies have not reported on its cognitive effects. Studies in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma A, levels, and a recent study in healthy subjects demonstrated a robust, dose-dependent inhibition of newly generated A, in the CSF after single oral doses. Conclusions: Unfortunately, ,-secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes, and alterations in hair color, effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation. Nevertheless, at least other two promising ,-secretase inhibitors are being tested clinically. This class of drugs represents a major hope to slow the rate of decline of AD. [source] | ||||||||||||||||