Browsing by Subject "Amyloid beta-Peptides"
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Item AB1-42 Antibody Producing Plasma Cells in DNA AB42 Trimer Immunized Mice Reside Predominantly in the Bone Marrow(2013-01-22) Zacharias, Tresa; Langworthy, Suzanna; Fu, Min; Anderson, Larry; Stuve, Olaf; Rosenburg, Roger; Lambracht-Washington, DorisAlzheimer's disease (AD) is the most common form of age-related dementia and affects nearly 40 million people worldwide. Immunotherapy provides a possible avenue for prophylaxis of AD, but a clinical trial (AN1792) in which patients with early AD were immunized with Aβ1-42 peptide was halted after the occurrence of meningoencephalitis in 6% of the immunized people which was attributed to a T cell autoimmune response. DNA vaccination has been shown to have a polarized Th2 immune response that lacks many of the features responsible for inflammation seen in peptide immunizations. In this study, we show a new feature of the DNA Aβ42 trimer elicited B cell immune response and present data for the presence of a long lived plasma cell pool residing within the bone marrow in DNA immunized mice but not in peptide immunized mice. Two groups of mice were analyzed: one group of B6C3F1 mice (n=20) were studied 4 months after the last DNA vaccination, and a second group of BALB/c mice (n=14), which received DNA or peptide immunizations, were analyzed 10 days following the last immunization. The comparison of antibody producing cells in bone marrow and spleen for the DNA and peptide immunized mice with an Antibody Forming Cell (AFC) ELISPOT assay and subsequent ELISAs showed that bone marrow plasma cells from DNA immunized mice produced more anti-Aβ42 IgG producing cells and higher levels of secreted IgG antibodies. In peptide immunized mice, more IgG antibody producing cells were found to reside in the spleen. These data indicate that the bone marrow may be an important reservoir for B cells following DNA Aβ42 immunization and is in line with studies showing that the bone marrow represents an excellent niche for the survival of long lived plasma cells and a lifetime source for antibody producing B cells which are independent of continuous antigen specific stimulation. Further studies are needed to show whether it is possible to define additional phenotypic characteristics for the antigen specific B cell immune response in DNA Aβ42 trimer immunized mice or differences in the TH subsets directly involved in initial signaling events to B cells in the germinal center reactions.Item Analyses of the Link Between Amyloid and Tau Pathology in an AD Mouse Model (3xtg-AD): Disease Progression with Increased Levels of Abeta and Tau Peptides(2018-01-23) Zapata, Lucio, Jr.; Ismail, Hannah; Lambracht-Washington, DorisINTRODUCTION: Pathological features of Alzheimer's disease (AD) include the accumulation of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptide and intracellular neurofibrillary tangles consisting of phosphorylated tau protein. Mutations in the genes that encode amyloid precursor protein (APP), and presenilin 1 and 2 (PS1/PS2) have been shown to cause familial AD in humans. Studies provided evidence that Aβ accumulation may initiate phosphorylation of tau protein, via the Ras/MEK/Extracellular Signal-regulated Kinase (ERK) signaling cascade, activation of the mitogen-activated protein kinase (p38 MAPK), Cyclin dependent kinase 5 (CDK5) and/or glycogen synthase kinase-3β (GSK3β). We studied distribution of Aβ and tau oligomers, Erk activity in different brain lysate fractions from different age groups of a triple transgenic mouse model (3xTg-AD) and wild-type mice, and Erk activity in DNA Abeta42 immunized mice. METHODS: Brain lysates of 4-, 6-, 12-, and 20-month-old 3xTg-AD and wild-type mice were prepared via a 4-step extraction protocol in TBS (soluble), TBS-T, SDS, and formic acid. DNA Abeta42 vaccination administered via gene gun. Abeta and Tau concentrations and Tau phosphorylation levels were monitored by Dot blot, Semidenaturing detergent agarose gel electrophoresis (SDD-AGE), and ELISA using anti-Abeta and anti-Tau antibodies. Erk1/2 levels were monitored by Western blot using monoclonal antibodies. RESULTS: There was a significant increase of total tau concentrations with increasing age and we found also an increasing insolubility (more tau in the non-soluble brain lysate fractions). 4- and 20-month-old 3xTg-AD soluble brain lysates indicated the presence of aggregated tau peptide, which was not present in wild-type control mice. Kinases involved with tau phosphorylation were measured and showed an increase of activated/phosphorylated Erk1/2 with increasing age, with a drop in concentration at 12 months in half of the mice analyzed (n=5). Immunized 3xTg-AD mice showed a decrease in activated Erk1/2 when compared to non-immunized, age matched mice. DISCUSSION: The 3xTg-AD mouse model provides a good model to study pathologies and possible treatments for human Alzheimer's disease. Abeta 42 peptide and tau increase due to age in this mouse model. A link between the amyloid pathology is likely found in the wide spectrum of cellular kinases which are upregulated due to Abeta in Alzheimer's disease. Therefore, immunization against Abeta and generation of anti-Abeta antibody will indirectly reduce tau pathology.