Showing papers by "Donald L. Price published in 2001"

BACE1 is the major beta-secretase for generation of Abeta peptides by neurons.

Abstract: Two β-secretases, BACE1 and BACE2, are involved in generation of Alzheimer's disease Aβ peptides1,2,3. We report that secretion of Aβ peptides (Aβ1–40/42 and Aβ11–40/42) is abolished in cultures of BACE1-deficient embryonic cortical neurons, and that whereas both human and murine BACE1 can cleave either human or murine β-amyloid precursor protein (APP) at the +1 site of Aβ, cleavage at the +11 site is species specific. We establish that BACE1 is the principal neuronal protease required to cleave APP at +1 and +11 sites that generate N-termini of Aβ.

β-Amyloid Peptide Vaccination Results in Marked Changes in Serum and Brain Aβ Levels in APPswe/PS1ΔE9 Mice, as Detected by SELDI-TOF-Based ProteinChip® Technology

Abstract: Although the pathogenesis of Alzheimer's disease (AD) is not fully understood, growing evidence indicates that the deposition of beta-amyloid (Abeta) and the local reactions of various cell types to this protein play major roles in the development of the disease. Immunization with the Abeta 1-42 peptide has been reported to decrease Abeta deposits in the brains of mutant amyloid precursor protein (APP/V717F) transgenic (tg) mice (Schenk et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-177). We have replicated this finding in APPswe/PS1DeltaE9 tg mice, which also develop Abeta deposits in the brain. The immunized animals developed high titers of antibodies against Abeta 1-42 in serum, and Abeta deposits in the brains were significantly reduced. Using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry and ProteinChip((R)) technology, we detected trends toward increased soluble Abeta peptide in the brain and a decrease in assayable Abeta peptide in the serum of immunized compared with control animals. This last finding raises the possibility that anti-Abeta antibodies in the periphery sequester Abeta peptides or target them for degradation and in this way contribute to the enhanced Abeta clearance from the brain in immunized animals.

Hyper-expression of human apolipoprotein E4 in astroglia and neurons does not enhance amyloid deposition in transgenic mice

Abstract: Recent studies in mice have clearly demonstrated that eliminating Apo E alters the rate, character and distribution of A beta deposits. In the present study, we asked whether elevating the levels of Apo E can, in a dominant fashion, influence amyloid deposition. We expressed human (Hu) Apo E4 via the mouse prion protein promoter, resulting in high expression in both astrocytes and neurons; only astrocytes efficiently secreted Hu Apo E4 (at least 5-fold more than endogenous). Mice hyper-expressing Hu Apo E4 developed normally and lived normal lifespans. The co-expression of Hu Apo E4 with a mutant amyloid precursor protein (APP) (Mo/Hu APPswe) or mutant APP and mutant presenilin (PS1dE9) did not lead to proportional changes in the age of appearance, relative burden, character or distribution of A beta deposits. We suggest that these data are best explained by proposing that the mechanisms by which Apo E influences A beta deposition involves an aspect of its normal function that is not augmented by hyper-expression.

Beta-secretase transgenic organisms, anti-beta-secretase antibodies, and methods of use thereof

Abstract: Transgenic non-human animals, including, for example, transgenic rodents and transgenic non-human mammalian cells, which harbor a transgene that eliminates the expression of the β-secretase, BACE1, are provided. In addition, antibodies specific for BACE1 are provided. Also provided are methods of diagnosing a neurodegenerative disease, including Alzheimer's disease, and methods of identifying agents that modulate or treat Alzheimer's disease, and methods of identifying agents that modulate or treat Alzheimer's disease and related pathology.

Genetically engineered models relevant to neurodegenerative disorders: their value for understanding disease mechanisms and designing/testing experimental therapeutics.

Abstract: Significant progress in the identification of disease-specific genes for a variety of neurodegenerative diseases have provided opportunities to understand molecular mechanisms and to test experimental therapeutic for these disorders. Recent works on clarifying the selective vulnerability of neurons and pathogenic mechanisms using genetically engineered mouse models of familial forms of Alzheimer’s disease and motor neuron disease will be reviewed.

The brain's susceptibility to amyloid plaques.

Abstract: Among the most challenging mysteries of Alzheimer's disease is the identification of factors that render the brain particularly susceptible to the extracellular deposition of β-amyloid (Aβ). Aβ peptides are thought to be toxic and are the central component of neuritic plaques, which are

Experimental Genetics as a Tool for Understanding Pathogenesis of ALS

Abstract: The identification of genes linked to a variety of neurodegenerative diseases allows the examination of the pathogenic mechanisms underlying these illnesses. The use of transgenic and gene-targeted mice approaches has allowed investigators to perturb the normal pattern of gene expression in mammals and to determine the phenotypic consequences of expressing wild-type/mutant genes linked to neurodegenerative diseases. Over the past decade, transgenic mice strategies have allowed researchers to reproduce features of human neurodegenerative disease in mice, and among the various models, the mutant superoxide dismutase-1 (SOD-1) mice—a model of familial amyotrophic lateral sclerosis (FALS)—has become a prototype for investigations of mechanisms of selective neuronal degeneration. In this chapter, we will discuss briefly the clinical, genetic, and neuropathological features of ALS, and illustrate how transgenic approaches are valuable tools for testing the role of copper in the pathogenesis of SOD-1-linked ALS. The delivery of copper to SOD-1 in yeast is mediated through a soluble protein called CCS (copper chaperone for SOD-1) and by generating CCS-deficient mice, we document that CCS is necessary to selectively deliver copper to SOD-1 to activate this mammalian metalloenzyme. These CCS knockout mice are valuable, in crossbreeding studies using mutant SOD-1 mice, to test directly whether copper in mutant SOD-1 is critical to cause motor-neuron degeneration in SOD-1-linked FALS. Finally, we will review the lessons we have learned from the SOD-1 transgenic mice models regarding the pathogenic mechanisms of FALS.

Organismes transgeniques de la beta-secretase, anticorps anti-beta-secretase, et methodes d'utilisation correspondantes

Abstract: La presente invention concerne des animaux non humains transgeniques, notamment, par exemple des rongeurs transgeniques et des cellules mammaliennes non humaines transgeniques abritant un transgene qui elimine l'expression de la β-secretase, BACE1. En outre, cette invention a trait a des anticorps specifiques de BACE1, a des methodes de diagnostic d'une maladie neurodegenerative, y compris la maladie d'Alzheimer, et a des methodes d'identification d'agents modulant ou traitant la maladie d'Alzheimer et la pathologie afferente.