Alzheimer's disease (AD) is characterized by the accumulation of intraneuronal tau and extracellular amyloid-β (Aβ) peptide. A triple transgenic (Tg) mouse (3xTg-AD) was reported to develop Aβ plaques and tau inclusions as well as remarkable accumulations of intracellular Aβ that were suggested to be the initiators of AD pathogenesis. However, it was unclear whether the anti-Aβ antibodies were able to distinguish Aβ peptide from the same Aβ epitopes within the amyloid precursor protein (APP). To further elucidate the identity of the immunoreactive intraneuronal material in 3xTg-AD mice, we conducted immunohistochemical, biochemical, and ultrastructural studies using a well characterized panel of antibodies that distinguish Aβ within APP from cleaved Aβ peptides. We found that the intraneuronal material shared epitopes with full-length APP but not free Aβ. To demonstrate unequivocally that this intraneuronal material was not free Aβ peptide, we generated 3xTg-AD mice deficient for β-secretase (BACE), the protease required for Aβ generation from APP. In the absence of Aβ production, robust intraneuronal APP immunostaining was detected in the 3xTg-AD/BACE(-/-) mice. Finally, we found that the formation of tau lesions was not different between 3xTg-AD versus 3xTg-AD/BACE(-/-) mice, thereby demonstrating that tau pathology forms independently from Aβ peptide generation in this mouse model. Although we cannot corroborate the presence of intraneuronal Aβ peptide in 3xTg-AD mice, our findings warrant further study as to the role of aberrant APP accumulation in this unique model of AD.
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http://dx.doi.org/10.1523/JNEUROSCI.6637-10.2011 | DOI Listing |
J Biol Chem
February 2023
Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan, USA. Electronic address:
The Saccharomyces cerevisiae Yta7 is a chromatin remodeler harboring a histone-interacting bromodomain (BRD) and two AAA+ modules. It is not well understood how Yta7 recognizes the histone H3 tail to promote nucleosome disassembly for DNA replication or RNA transcription. By cryo-EM analysis, here we show that Yta7 assembles a three-tiered hexamer with a top BRD tier, a middle AAA1 tier, and a bottom AAA2 tier.
View Article and Find Full Text PDFJ Med Chem
June 2006
Division of Organic Chemistry and Biochemistry, Ruder Bosković Institute, POB 180, 10002 Zagreb, Croatia.
A series of new peptides (8-25) containing different unnatural amino acids of the adamantane type (1-6), was synthesized. Possible cytotoxic activity on human cervical adenocarcinoma (HeLa), larynx carcinoma (HEp-2), colon carcinomas (HT-29, Caco-2), poorly differentiated cells from lymph node metastasis of colon carcinoma (SW-620), mammary gland adenocarcinoma (MCF-7), and melanoma (HBL) cells were tested by the MTT assay. The results were compared with the effect of methionine-enkephalin (Tyr-Gly-Gly-Phe-Met, or opioid growth factor, OGF), and its shorter N-terminal fragments.
View Article and Find Full Text PDFJ Pept Sci
October 2003
Laboratory of Peptides, Department of Chemistry, Warsaw University, Pasteura 1, Warsaw, 02-093 Poland.
A new family of cyclic opioid peptide analogues related to the 1-4 sequence of dermorphin/deltorphin (Tyr-D-Aaa2-Phe-Aaa4-NH2) has been synthesized. The synthesis of the linear precursor peptides was accomplished by the solid-phase method and ring formation was achieved via a ureido group incorporating the side chain amino functions of D-Aaa2 (D-Lys, D-Orn) and Aaa4 (Lys, Orn, Dab, Dap). The peptides were tested in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays.
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