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Todd E Golde

Publications and source records attributed to Todd E Golde.

47 records · Page 3Linked to original sources
PubMed2003

Immune responses against Abeta1-42 in HLA class II transgenic mice: implications for Abeta1-42 immune-mediated therapies.

We have investigated whether polymorphic differences in the major histocompatibility complex (MHC) class II molecules influence humoral and cellular immune responses against Abeta1-42. To analyze the effects of mouse MHC class II and tolerance effects of overexpression of human APP in mice, we immunized Tg2576 and non-transgenic littermates bred into two different MHC backgrounds with Abeta1-42 and compared both B and T cell responses. We found that in the presence of the mouse C57BL/6 background, both B and T cell responses against Abeta1-42 were significantly suppressed. To directly test the contribution of human MHC class II, we immunized various human HLA class II transgenic (TG) mice with Abeta1-42 and analyzed anti-Abeta immune responses. HLA-DR3 and HLA-DQ8 TG mice generated modest B and T cell responses against Abeta1-42. The presence of HLA-DR3/DQ8 in double TG mice enhanced the overall immune response against Abeta1-42. In contrast, HLA-DR4 TG mice mounted strong T cell responses but failed to generate high titer antibody responses against Abeta1-42, whereas, the HLA-DQ6 TG mice were not able to mount significant B or T cell responses against Abeta1-42. These studies in mice suggest that the presence of certain MHC class II molecules or combinations of class II molecules can potentially influence the overall immune response against Abeta1-42.

Amyloid beta-Peptides↗
PubMed2003

NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.

Alzheimer Disease↗
PubMed2002

Identification of a novel family of presenilin homologues.

Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. Presenilins have been shown to influence limited proteolysis of amyloid beta protein precursor (APP), Notch and ErbB4, and have been proposed to be gamma-secretases that perform the terminal cleavage of APP. In this model, two conserved and apparently intramembranous aspartic acids participate in catalysis. Highly sequence-similar presenilin homologues are known in plants, invertebrates and vertebrates. In this work, we have used a combination of different sequence database search methods to identify a new family of proteins homologous to presenilins. Members of this family, which we term presenilin homologues (PSH), have significant sequence similarities to presenilins and also possess two conserved aspartic acid residues within adjacent predicted transmembrane segments. The PSH family is found throughout the eukaryotes, in fungi as well as plants and animals, and in archaea. Five PSHs are detectable in the human genome, of which three possess "protease-associated" domains that are consistent with the proposed protease function of PSs. Based on these findings, we propose that PSs and PSHs represent different sub-branches of a larger family of polytopic membrane-associated aspartyl proteases.

Alzheimer Disease↗
PubMed2002

Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle.

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.

Amyloid beta-Protein Precursor↗
PubMed2002

A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP.

Presenilins mediate an unusual intramembranous proteolytic activity known as gamma-secretase, two substrates of which are the Notch receptor (Notch) and the beta-amyloid precursor protein (APP). Gamma-secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [APP intracellular domain (AICD)] that forms a transcriptively active complex. We now demonstrate a functional role for AICD in regulating phosphoinositide-mediated calcium signaling. Genetic ablation of the presenilins or pharmacological inhibition of gamma-secretase activity (and thereby AICD production) attenuated calcium signaling in a dose-dependent and reversible manner through a mechanism involving the modulation of endoplasmic reticulum calcium stores. Cells lacking APP (and hence AICD) exhibited similar calcium signaling deficits, and-notably-these disturbances could be reversed by transfection with APP constructs containing an intact AICD, but not by constructs lacking this domain. Our findings indicate that the AICD regulates phosphoinositide-mediated calcium signaling through a gamma-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.

Amyloid Precursor Protein Secretases↗
PubMed2002

FAD-linked mutations in presenilin 1 alter the length of Abeta peptides derived from betaAPP transmembrane domain mutants.

gamma-Secretase is an enzymatic activity responsible for the final cleavage of the amyloid precursor protein leading to the production of the amyloid beta-peptide (Abeta). gamma-Secretase is likely an aspartyl protease, since its activity can be inhibited by both pepstatin and active-site directed aspartyl protease inhibitors. Recent work has indicated that presenilins 1 and 2 may actually be the gamma-secretase enzymes. Presenilin (PS) mutations, which lead to an increase in the production of a longer form of Abeta, are also the most common cause of familial Alzheimer's disease (FAD). Therefore, in an attempt to better characterize the substrate preferences of gamma-secretase, we performed experiments to determine how FAD-linked mutations in PS1 would affect the generation of Abeta peptides from full length precursor substrates that we have previously demonstrated to be proteolytically cleaved at alternative sites and/or by enzymatic activities that are pharmacologically distinct. Presenilin mutations increased the production of Abeta peptides from sites distal to the primary cleavage site ('longer' peptides) and in several cases also decreased production of 'shorter' peptides. These results support a model in which the FAD-linked mutants subtly alter the conformation of the gamma-secretase complex to favor the production of long Abeta.

Amino Acid Sequence↗
PubMed2002

Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains.

Buoyant membrane fractions containing presenilin 1 (PS1), an essential component of the gamma-secretase complex, and APP CTFbeta, a gamma-secretase substrate, can be isolated from cultured cells and brain by several different fractionation procedures that are compatible with in vitro gamma-secretase assays. Analysis of these gradients for amyloid beta protein (Abeta) and CTFgamma production indicated that gamma-secretase activity is predominantly localized in these buoyant membrane microdomains. Consistent with this localization, we find that gamma-secretase activity is cholesterol dependent. Depletion of membrane cholesterol completely inhibits gamma-secretase cleavage, which can be restored by cholesterol replacement. Thus, altering cholesterol levels may influence the development of Alzheimer's disease (AD) by influencing production and deposition of Abeta within cholesterol rich membrane microdomains.

Alzheimer Disease↗
PubMed2002

A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch.

A novel presenilin 1 mutation, insR352, associated with a frontal temporal dementia phenotype has been identified (E. A. Rogaeva et al., 2001, Neurology 57, 621-625). This mutation does not increase Abeta42 levels, but instead acts as dominant negative presenilin, decreasing amyloid beta protein (Abeta) production by inhibiting gamma-secretase cleavage of the Abeta precursor. The distinct clinical phenotype associated with this mutation suggests that chronic partial inhibition of gamma-secretase activity may result in neurodegeneration.

Amyloid Precursor Protein Secretases↗