[Originally published in Synapse on September 17, 1998.]
Research leading to treatments of Alzheimer’s disease, stroke and HIV-associated dementia will be the focus of UCSF’s new Gladstone Institute of Neurological Disease, which was inaugurated with a symposium.
Director Lennart Mucke pointed out that as the average lifespan increases, age-related neurological diseases will become a more widespread medical problem. The new Institute will pursue both preventative and palliative solutions, as well as basic research, Mucke said.
Mucke introduced Nobel Prize winner Stanley Prusiner as “the major driving force behind research into neurodegenerative diseases at UCSF.” Prusiner spoke on how abnormal folding of prion proteins can underlie disorders like kuru, Creutzfedlt-Jacob disease, and Gertsmann-Straussler-Scheinker disease.
Although the new institute will not locus on the pathogenesis of these prion diseases. Prusiner’s research is important because the finding that inappropriate protein conformations can cause disease suggests an etiology for other neurodegenerative illnesses.
In fact, as Prusiner pointed out, prion diseases share similarities with Alzheimer’s: the majority of cases arise sporadically, pathologic protein deposits are seen upon autopsy, and the diseases appear to dodge immune surveillance effectively.
Apolipoproteins and Alzheimer’s
Investigators have implicated apolipoproteins — molecules mediating the transport and storage of cholesterol — in the development of Alzheimer’s. Two variations of the apolipoprotein exist, known as apoE3 and apoE4.
Because our bodies contain two copies of each chromosome, an individual may inherit two copies of apoE3, two copies of apoE4, or one copy of each. Scientists have understood that people who inherit two copies of apoE4 are at greater risk for developing Alzheimer’s than those who receive two copies of apoE3.
Mucke and his group recently published the results of a study in which genetically altered mice expressing either human apoE3 or apoE4 underwent a battery of tests assessing specific cognitive abilities. The apoE4 mice performed poorly in exercises testing memory and spatial relationships.
A similar loss of functional memory is seen among people with Alzheimer’s, leading Mucke to feel “very excited” about the prospect of using these mice to evaluate potential therapies. The study is featured in the Sept. 1 issue of Proceedings of the National Academy of sciences.
More models
A few years ago, Mucke described how amyloid precursor protein (APP) may be neuroprotective against pericellular insults (like excitatory ammo acids).
He has subsequently worked with Dora Games and a team of scientists at Athena Neurosciences on the characterization of a mouse model that would mimic neurodegenerative processes seen in Alzheimer’s.
They have been able to show that a fragment of the amyloid precursor protein called A-B accumulates and forms plaques in the brains of Alzheimer’s patients, and that their transgenic mice also develop these classical plaques.
In past research on HIV-associated dementia, Mucke has looked at mice that produce a protein called gpl2o that the human immunodeficiency virus (HIV) uses to dock on T-lymphocytes and macrophages, cells that contribute to cellular immunity.
Astrocytes (support cells of the central nervous system) were designed to secrete gpl2o, which may then bind pathologically to astrocytes and other cells. He and his colleagues showed that neurodegeneration in the brains of these transgenic mice (engineered to make a specific protein) mimicked that seen in the autopsied brains of patients with AIDS-related dementia in a dose-dependent way.
Mucke will be working in concert with Bruce Miller, MD, who will head clinical efforts at the new institute. Miller is clinical director of the aging and dementia program at UCSF/Mount Zion and medical director of the John Douglas French Foundation for Alzheimer’s Disease Research in Los Angeles.
At a press conference held during a break in the symposium, Miller said, “My longterm goal is that we’re no longer robbed of the wisest of our population — the elderly.”
Three’s Company
The J. David Gladstone Institutes “were created by a 1971 bequest of $8 million from a Bay Area real estate developer to a trust for medical research. In addition to the new Neurological Diseases branch, there’s the Gladstone Institute of Virology and Immunology, which conducts AIDS research, and the Institute of Cardiovascular Disease, which studies aspects of coronary artery disease.
Some 17 principal investigators and more than 230 post-docs, students, and volunteers work in Gladstone-funded labs and offices at San Francisco General Hospital and UCSF.
