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Dale E Bredesen

Publications and source records attributed to Dale E Bredesen.

At least 19 recordsLinked to original sources
PubMed2006

Deficits in synaptic transmission and learning in amyloid precursor protein (APP) transgenic mice require C-terminal cleavage of APP.

Synaptic dysfunction has been shown to be one of the earliest correlates of disease progression in animal models of Alzheimer's disease. Amyloid-beta protein (Abeta) is thought to play an important role in disease-related synaptic dysfunction, but the mechanism by which Abeta leads to synaptic dysfunction is not understood. Here we describe evidence that cleavage of APP in the C terminus may be necessary for the deficits present in APP transgenic mice. In APP transgenic mice with a mutated cleavage site at amino acid 664, normal synaptic transmission, synaptic plasticity, and learning were maintained despite the presence of elevated levels of APP, Abeta42, and even plaque accumulation. These results indicate that cleavage of APP may play a critical role in the development of synaptic and behavioral dysfunction in APP transgenic mice.

Alzheimer Disease↗
PubMed2006

Cell death in the nervous system.

Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease trigger neuronal cell death through endogenous suicide pathways. Surprisingly, although the cell death itself may occur relatively late in the course of the degenerative process, the mediators of the underlying cell-death pathways have shown promise as potential therapeutic targets.

Animals↗
PubMed2006

Differential regulation of the intrinsic pathway of apoptosis in brain and liver during ageing.

The intrinsic (mitochondria-dependent) pathway of apoptosis is one of the major pathways leading to cell death. We evaluated cytochrome c/apoptotic protease activation factor-1 (Apaf-1)-dependent activation of caspase-3 in brain and liver of different strains of rodents at different stages of development. In cell-free extracts from brain and liver of Sprague-Dawley rats, caspase was activated by cytochrome c/2'-deoxyadenosine 5'-triphosphate at both neonatal and adult stages. In adult brain extracts from Wistar rats, no activation of caspase was observed while extracts from neonatal brain and liver and from adult liver were activated. In CD-1 mouse, only neonatal extracts were activated. Alteration in levels of endogenous inhibitors of apoptosis were not responsible for the lack of activation observed. Instead, decrease in the content of Apaf-1 and caspase-3 and some degradation of caspase-9 during brain ageing were observed. These results suggest that a decrease in apoptosis activation during ageing is not tissue-specific, but rather displays a complex dependence on species and strains of animals.

Aging↗
PubMed2006

Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664.

The deficits characteristic of Alzheimer's disease (AD) are believed to result, at least in part, from the neurotoxic effects of beta-amyloid peptides, a set of 39-43 amino acid fragments derived proteolytically from beta-amyloid precursor protein (APP). APP also is cleaved intracytoplasmically at Asp-664 to generate a second cytotoxic peptide, APP-C31, but whether this C-terminal processing of APP plays a role in the pathogenesis of AD is unknown. Therefore, we compared elements of the Alzheimer's phenotype in transgenic mice modeling AD with vs. without a functional Asp-664 caspase cleavage site. Surprisingly, whereas beta-amyloid production and plaque formation were unaltered, synaptic loss, astrogliosis, dentate gyral atrophy, increased neuronal precursor proliferation, and behavioral abnormalities were completely prevented by a mutation at Asp-664. These results suggest that Asp-664 plays a critical role in the generation of Alzheimer-related pathophysiological and behavioral changes in human APP transgenic mice, possibly as a cleavage site or via protein-protein interactions.

Alzheimer Disease↗
PubMed2005

Developmental shift in the apostat: comparison of neurones and astrocytes.

The intrinsic pathway of apoptosis was investigated in cell-free extracts of neurones and astrocytes at various stages of maturation. Neuronal extracts were activated 65-fold after 3 days, 9-fold after 7 days, and were not activated after 10 days in culture. In contrast, astrocyte extracts were activated to a similar extent at all stages, up to 60 days in culture. The co-incubation of neuronal and astrocyte extracts followed by addition of cytochrome c/2'-deoxyadenosine 5'-triphosphate led to a 40-fold activation, suggesting that the development-associated neuronal shift does not involve the appearance of a dominant inhibitor, but rather downregulation of some key component(s) involved in caspase activation.

Animals↗
PubMed2005

Improved prediction of critical residues for protein function based on network and phylogenetic analyses.

BACKGROUND: Phylogenetic approaches are commonly used to predict which amino acid residues are critical to the function of a given protein. However, such approaches display inherent limitations, such as the requirement for identification of multiple homologues of the protein under consideration. Therefore, complementary or alternative approaches for the prediction of critical residues would be desirable. Network analyses have been used in the modelling of many complex biological systems, but only very recently have they been used to predict critical residues from a protein's three-dimensional structure. Here we compare a couple of phylogenetic approaches to several different network-based methods for the prediction of critical residues, and show that a combination of one phylogenetic method and one network-based method is superior to other methods previously employed. RESULTS: We associate a network with each member of a set of proteins for which the three-dimensional structure is known and the critical residues have been previously determined experimentally. We show that several network-based centrality measurements (connectivity, 2-connectivity, closeness centrality, betweenness and cluster coefficient) accurately detect residues critical for the protein's function. Phylogenetic approaches render predictions as reliable as the network-based measurements, although, interestingly, the two general approaches tend to predict different sets of critical residues. Hence we propose a hybrid method that is composed of one network-based calculation--the closeness centrality--and one phylogenetic approach--the Conseq server. This hybrid approach predicts critical residues more accurately than the other methods tested here. CONCLUSION: We show that network analysis can be used to improve the prediction of amino acids critical for protein function, when utilized in combination with phylogenetic approaches. It is proposed that such improvement is due to the complementary nature of these approaches: network-based methods tend to predict as critical those residues that are highly connected and internal (i.e., non-surface), although some surface residues are indeed identified as critical by network analyses; whereas residues chosen by phylogenetic approaches display a lower overall probability of being surface inaccessible.

Computational Biology↗
PubMed2005

A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease.

Several approaches have been used in an effort to identify proteins that interact with beta-amyloid precursor protein (APP). However, few studies have addressed the identification of proteins associated with APP in brain tissue from patients with Alzheimer's disease. We report the results of a pilot proteomic study performed on complexes immunoprecipitated with APP in brain samples of patients with Alzheimer's disease and normal control subjects. The 21 proteins identified could be grouped into five functional classes: molecular chaperones, cytoskeletal and structural proteins, proteins involved in trafficking, adaptors, and enzymes. Among the proteins identified, six had been reported previously as direct, indirect, or genetically inferred APP interactors. The other 15 proteins immunoprecipitated with APP were novel potential partners. We confirmed the APP interaction by Western blotting and coimmunolocalization in brain tissues, for 5 of the 21 interactors. In agreement with previous studies, our results are compatible with an involvement of APP in axonal transport and vesicular trafficking, and with a potential association of APP with cellular protein folding/protein degradation systems.

Alzheimer Disease↗
PubMed2004

Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.

The expression of the protein DCC (deleted in colorectal cancer) is lost or markedly reduced in numerous cancers and in the majority of colorectal cancers due to loss of heterozygosity in chromosome 18q, and has therefore been proposed to be a tumour suppressor. However, the rarity of mutations found in DCC, the lack of cancer predisposition of DCC mutant mice, and the presence of other tumour suppressor genes in 18q have raised doubts about the function of DCC as a tumour suppressor. Unlike classical tumour suppressors, DCC has been shown to induce apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless DCC is engaged by its ligand, netrin-1 (ref. 3). Here we show that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract leads to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engenders aggressive adenocarcinomatous malignancies. These data demonstrate that netrin-1 can promote intestinal tumour development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumour suppressors.

Adenocarcinoma↗
PubMed2004

Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice.

Neurogenesis continues in the adult brain and is increased in certain pathological states. We reported recently that neurogenesis is enhanced in hippocampus of patients with Alzheimer's disease (AD). We now report that the effect of AD on neurogenesis can be reproduced in a transgenic mouse model. PDGF-APP(Sw,Ind) mice, which express the Swedish and Indiana amyloid precursor protein mutations, show increased incorporation of BrdUrd and expression of immature neuronal markers in two neuroproliferative regions: the dentate gyrus and subventricular zone. These changes, consisting of approximately 2-fold increases in the number of BrdUrd-labeled cells, were observed at age 3 months, when neuronal loss and amyloid deposition are not detected. Because enhanced neurogenesis occurs in both AD and an animal model of AD, it seems to be caused by the disease itself and not by confounding clinical factors. As neurogenesis is increased in PDGF-APP(Sw,Ind) mice in the absence of neuronal loss, it must be triggered by more subtle disease manifestations, such as impaired neurotransmission. Enhanced neurogenesis in AD and animal models of AD suggests that neurogenesis may be a compensatory response and that measures to enhance neurogenesis further could have therapeutic potential.

Alzheimer Disease↗
PubMed2004

Alternative, nonapoptotic programmed cell death: mediation by arrestin 2, ERK2, and Nur77.

Programmed cell death (pcd) may take the form of apoptosis or of nonapoptotic pcd. Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the mediators of nonapoptotic cell death programs are much less well characterized. Here we report that alternative, nonapoptotic pcd induced by the neurokinin-1 receptor (NK(1)R) activated by its ligand Substance P, is mediated by a MAPK phosphorylation cascade recruited by the scaffold protein arrestin 2. The activation of the protein kinases Raf-1, MEK2, and ERK2 is essential for this form of nonapoptotic pcd, leading to the phosphorylation of the orphan nuclear receptor Nur77. NK(1)R-mediated cell death was inhibited by a dominant negative form of arrestin 2, Raf-1, or Nur77, by MEK1/2-specific inhibitors, and by RNA interference directed against ERK2 or MEK2 but not ERK1 or MEK1 and against Nur77. The MAPK pathway is also activated in neurons in primary culture undergoing NK(1)R-mediated death, since the MEK inhibitor PD98059 inhibited Substance P-induced death in primary striatal neurons. These results suggest that Nur77, which is regulated by a MAPK pathway activated via arrestin 2, modulates NK(1)R-mediated nonapoptotic pcd.

Animals↗
PubMed2004

siRNA-based inhibition specific for mutant SOD1 with single nucleotide alternation in familial ALS, compared with ribozyme and DNA enzyme.

In many of autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with SOD1 mutation, a missense point mutation may induce the disease by its gain of adverse property. Reduction of such a mutant protein expression is expected to improve the disease phenotype. Duplex of 21-nt RNA, known as siRNA, has recently emerged as a powerful tool to silence gene, but the sequence specificity and efficacies have not been fully studied in comparison with ribozyme and DNA enzyme. We could make the siRNA which recognized even a single nucleotide alternation and selectively suppress G93A SOD1 expression leaving wild-type SOD1 intact. In mammalian cells, the siRNA much more efficiently suppressed the expression of mutant SOD1 than ribozyme or DNA enzyme. Furthermore, these siRNAs could suppress cell death of Neuro2a induced by over-expression of mutant SOD1s with stress of proteasome inhibition. Our results support the feasibility of utilizing siRNA-based gene therapy of familial ALS with mutant SOD1.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Misfolded proteins, endoplasmic reticulum stress and neurodegeneration.

The accumulation of misfolded proteins (e.g. mutant or damaged proteins) triggers cellular stress responses that protect cells against the toxic buildup of such proteins. However, prolonged stress due to the buildup of these toxic proteins induces specific death pathways. Dissecting these pathways should be valuable in understanding the pathogenesis of, and ultimately in designing therapy for, neurodegenerative diseases that feature misfolded proteins.

Animals↗
PubMed2004

Molecular characterization of neurohybrid cell death induced by Alzheimer's amyloid-beta peptides via p75NTR/PLAIDD.

One of the most important pathological features of Alzheimer's disease (AD) is extracellular senile plaques, whose major component is amyloid-beta peptides (Abeta). Abeta binds to the extracellular domain of p75NTR (p75 neurotrophin receptor) and induces neuronal cell death. We investigated the molecular mechanism of Abeta-induced neurotoxicity in detail from the standpoint of interaction between p75NTR and its recently identified relative, PLAIDD (p75-like apoptosis-inducing death domain). Using F11 neuronal hybrid cells, we demonstrate that there are two distinct pathways for Abeta-induced toxicity mediated by p75NTR. One pathway that has been previously elucidated, is mediated by p75NTR, Go, JNK, NADPH oxidase and caspase3-related caspases. We found that PLAIDD and Gi proteins, heterotrimeric G proteins, are involved in the alternative Abeta-induced neurotoxicity mediated by p75NTR. The alternative pathway triggered by Abeta is thus mediated by p75NTR, PLAIDD, Gi, JNK, NADPH oxidase and caspase3-related caspases. In addition, we found that HN, ADNF, IGF-I, or bFGF inhibits both pathways of Abeta-induced neurotoxicity mediated by p75NTR.

Alzheimer Disease↗
PubMed2004

The non-existent aging program: how does it work?

Summary Aging and lifespan determination have been viewed, in the most well-accepted theories, as nonprogrammatic, and are thought to result from the evolutionary selection for early fitness at the expense of late survival. Here, recent data implicating potentially programmatic aspects of aging and lifespan determination are discussed, and analogies between programmed cell death and programmed organismal death are offered. It is hoped that the recognition of at least the possibility of a programmatic aspect, or aspects, to the determination of longevity and the process of aging will help to optimize our chances to identify appropriate therapeutic targets both for longevity enhancement and disease prevention.

Aging↗
PubMed2004

Apoptosis and dependence receptors: a molecular basis for cellular addiction.

Classical signal transduction is initiated by ligand-receptor interactions. We have described an alternative form of signal transduction that is initiated by the withdrawal of ligands from specific receptors referred to as dependence receptors. This process is widespread, featuring in developmental cell death, carcinogenesis (especially metastasis), neurodegeneration, and possibly subapoptotic events such as neurite retraction and somal atrophy. Initial mechanistic studies of dependence receptors suggest that these receptors form complexes that include specific caspases. Complex formation appears to be a function of ligand-receptor interaction, and dependence receptors appear to exist in at least two conformational states. Complex formation in the absence of ligand leads to caspase activation by a mechanism that in at least some cases is dependent on caspase cleavage of the receptor itself, releasing proapoptotic peptides. Thus these receptors may serve in caspase amplification, and in so doing create cellular states of dependence on their respective ligands.

Animals↗
PubMed2004

Target-assisted iterative screening of phage surface display cDNA libraries.

The novel screening format, target-assisted iterative screening (TAIS), comprises a simple and rapid two-step procedure for in vitro affinity selection of specific binders from enormous molecular diversities to the target molecule of interest. This detailed protocol describes the application of TAIS to a T7 phage-displayed complementary DNA (cDNA) library with a protein domain as a target. Protocols for purification of the target as glutathione-S-transferase (GST) fusion protein and modifications of the purified target that are required for the screening complement the TAIS protocol. The described application is a method of choice for the researchers interested in the identification and characterization of novel protein-protein interactions mediated by peptide recognition domains.

Amino Acid Sequence↗
PubMed2004

Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex.

The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (beta-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1. Taken together with recent data demonstrating APP dimerization by beta-amyloid peptide (Abeta) (Lu et al., 2003), and the possible activation of ASK1 via APP dimerization (Hashimoto et al., 2003), these results suggest a model of AD in which Abeta peptide dimerizes APP directly, leading to the activation of ASK1, MKK6, and p38, with subsequent phosphorylation of tau at sites characteristic of AD.

Aged↗