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Source: Corinna Kaarlela
415-476-2557
11 September 1998
Major accomplishments: research community of the Gladstone Institute of Neurological Disease
Major accomplishments by GIND investigators and scientists during the past two years include:
Alzheimer’s Disease (AD)-related
· Demonstrated, in transgenic animal models and cultured neurons, that two variations of human apolipoprotein (apo) E—-called apoE3 and apoE4--have different effects on the structure and function of the central nervous system (CNS). ApoE is a molecule that allows cholesterol transported on lipoproteins to be taken up by various cells in the body.
· Showed that female gender increases the susceptibility to apoE4-induced CNS impairments.
· Established a transgenic animal model in which the expression of human apoE can be regulated (i.e., increased or decreased) to help predict the therapeutic benefit of apoE4-targeted drug treatments.
· Found that apoE3 and apoE4 accumulate to different extents in cultured neuronal cells.
· Demonstrated that a mutation associated with the familial form of AD reduces the ability of the amyloid B precursor protein (APP) to protect cells against apoptosis, or programmed cell death, a process that requires the expression of specific genes and the synthesis of proteins that participate in the destruction of the cell.
· Identified a possible cause-effect relationship between the overexpression of amyloid B--one of the products of APP which has been implicated in the development of AD--in neuronal cells and the degeneration of presynaptic terminals, which participate in the transmission of impulses from one neuron to another.
· Showed that transforming growth factor B1 (TGF-B1) is involved in the abnormal deposition of amyloid B in cerebral blood vessels, which is frequently seen in AD.
· Identified apoE as a potential mediator of cerebral amyloid deposition induced by TGF-B1.
· Demonstrated that apoE4 has a greater capacity than apoE3 to enhance amyloid-induced activation of complement. Complement refers to a complex of proteins in blood that are an important component of the immune system.
HIV Dementia-related
· Showed that increased expression of the human CD4 receptor on brain macrophages in persons with AIDS was associated with neurodegeneration and demonstrated that human CD4 can mediate neurodegeneration in brains of immune-challenged transgenic mice.
· Showed that expression of the HIV protein Nef in star-shaped brain cells, called astrocytes, disrupts their support of neuronal functions and results in the degeneration of interneurons. Interneurons are critical for the effective processing of information by the CNS.
· Found that when the HIV-1 envelope glycoprotein gp120--a protein that has detrimental effects on cultured nerve cells--is expressed in glial cells, it causes age-dependent impairments of spatial learning and memory in transgenic mice.
· Demonstrated that overexpression of TGF-B1 by astroglial cells can worsen the inflammation in the CNS in experimental models of multiple sclerosis.
Basic Neuroscience
· Showed that the amyloid precursor protein (APP) protects the CNS against certain types of neurotoxins that are presumed to damage nerve cells in acute and chronic diseases of the nervous system..
· Identified stimulated removal of excitatory amino acids by astroglial cells as a potential mechanism of the neuroprotective effects mediated by APP.
· Found that noninvasive environmental stimuli (exploration of a novel environment) in mice dramatically increases c-Jun kinase (JNK) activity in the CNS without causing neuronal death. This is in contrast to previous studies on cultured neurons, which had suggested that JNK activation might be an important trigger of neurodegeneration.
· Showed that damage to glial cells of the autonomous nervous system could be an important cause of inflammatory bowel diseases.
· Identified corticotropin-releasing factor and adrenocorticotrophic hormone as potential mediators of the effects of leptin on the CNS. Leptin is a protein factor that suppresses appetite and stimulates metabolism.
· Devised a new type of G protein-coupled receptor, called a RASSL (receptor activated solely by a synthetic ligand) that can be used to control G protein signaling in vivo. G protein-coupled receptors, the largest class of cell-surface receptors known, respond to a wide range of environmental stimuli (e.g., odorants, photons, lipids, and hormones). Activation of these receptors affects a broad range of physiological events, including heart rate, cell proliferation, neurotransmission, and hormone secretion.
· Demonstrated that a RASSL can control proliferation of tissue culture cells and heart rate in transgenic mice (overriding the mouse’s own neural mechanisms for controlling heart rate).
· Discovered some of the primary factors that determine the specificity of the interactions between G proteins and their receptors.
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