Scientists from the Gladstone Institute of Neurological Disease will present key findings in Alzheimer’s disease research at the World Alzheimer Congress 2000, July 9-18 at the Washington Hilton and Towers in Washington, DC.
This first-ever event is bringing together more than 5,000 scientific investigators and health care professionals from all parts of the globe for an international exchange of the latest information in three distinct program areas: pivotal research, bridging research and care, and creative care.
An estimated 4 million Americans now have Alzheimer’s disease (AD). Without a medical breakthrough, baby boomers reaching the age of highest risk-their mid-80s-could advance this number to 14 million by 2050.
Current research suggests that the accumulation of amyloid proteins in the brain and the inheritance of a particular apolipoprotein E gene (apoE4) may be the most important determinants in the development of AD, according to Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease (GIND) and professor of neurology at the University of California, San Francisco (UCSF). A greater understanding of the biology of these factors will facilitate the development of better drugs to prevent or slow the degeneration of brain cells that causes memory loss and disturbed behavior in this illness, Mucke emphasized.
In recent years, GIND investigators, all of whom are affiliated with UCSF, have begun to unravel how amyloid proteins and apoE4 could impair brain cells and cause age-related cognitive decline. Some of their most important work involves rapid progress in identifying therapeutic strategies that might prevent or inhibit these detrimental effects. To facilitate their studies, Gladstone investigators have developed a range of genetically altered (transgenic) mouse models that simulate various aspects of AD. These animal models make it possible to study and experimentally manipulate the course of the disease and to test the efficacy and safety of drug interventions.
Study findings by the GIND scientists to be reported at Alzheimer 2000 are as follows:
*Cell suicide link to AD— Luke Esposito, PhD, GIND post doctoral fellow. “Opposing Effects of the Abeta Peptide and Its Precursor Protein on the Proapoptotic p53 Pathway. “
The accumulation of amyloid proteins in the brain is a hallmark of Alzheimer’s disease but it remains unclear how exactly these proteins contribute to the loss of brain cells that always occurs in this illness. The investigators expressed amyloid proteins in cultured brain cells and found that the accumulation of amyloid proteins within neurons is not lethal by itself, but it makes these cells commit suicide when they are exposed to secondary age-related injuries. The amyloid-induced sensitization of cells could explain how increased production of amyloid proteins leads to degeneration of brain cells in AD patients and why the disease is so dependent on aging.
*The tangle of ApoE4 — Yadong Huang, MD, PhD, GIND staff research investigator and UCSF assistant professor of pathology. “Differential Effects of Cytosolic ApoE3 and ApoE4 on Neurite Outgrowth and the Cytoskeleton.”
Inheritance of the apoE4 gene increases the risk of developing Alzheimer’s, while the apoE3 gene makes people more resistant. Study results showed that when apoE4 was produced within cultured brain cells, it broke into fragments more often than apoE3. These fragments induced tangle-like fibers that resemble characteristic abnormalities found in Alzheimer brains. These findings suggest that apoE4 may contribute to brain cell damage by contorting the scaffold system that supports the structure of these cells.
*ApoE4 loses amyloid battle — Lennart Mucke, MD, GIND director and UCSF professor of neurology. “How Does ApoE4 Contribute to Alzheimer’s Disease? Clues from Transgenic Models.”
The contributions of amyloid proteins and apoE4 to Alzheimer’s were studied in transgenic mouse models. Research findings showed that apoE3 was able to prevent amyloid-induced memory deficits and to delay neurodegeneration in aging mice, but apoE4 was not. These results help to explain why people with apoE4 develop Alzheimer’s more often and earlier than people with apoE3. They also underline the potential usefulness of drugs that simulate beneficial apoE3 effects.
*Improving memory with sex steroids — Jacob Raber, PhD, GIND staff research scientist and UCSF assistant professor of neurology. “Improvement of Cognitive Deficits in Female ApoE4 Transgenic Mice After Treatment with Sex Steroids.”
Aging-related memory deficits and Alzheimer’s develop more often and earlier in people who have apoE4 than in people with apoE3, and women appear to be particularly susceptible to apoE4 effects. Potential therapies for apoE4-related memory deficits were tested in a transgenic mouse model. Treatment with male sex hormones dramatically improved apoE4-induced memory deficits in female mice, raising the possibility that sex hormones might also be effective in treating cognitive deficits in human apoE4 carriers.
*Changing outcome with drugs — Karl Weisgraber, PhD, GIND senior investigator and UCSF professor of pathology. “ApoE: Biology and Biochemistry.”
The study focused on a difference in the three-dimensional configuration of apoE variants that is known as domain interaction. It is unique to apoE4, and it might help to explain why apoE4 increases AD risk. Domain interaction was studied in a mouse model using a gene-targeting approach. Then computer modeling and biochemical assays identified several chemicals that interfered with domain interaction and made apoE4 act more like apoE3. In the future, these chemicals could be developed into drugs that might prevent or delay AD by blocking detrimental apoE4 activities.
*TGF-beta1, the insidious healer—Tony Wyss-Coray, PhD, GIND staff research investigator and UCSF assistant professor of neurology. “Transforming Growth Factor (TGF)-Beta1 Modifies Alzheimer’s-Type Pathology in Transgenic Mice and Humans. ”
The protein TGF-beta1 is known to help brain cells survive and heal following injury. However, when researchers looked at the relationship between TGF-beta1 genes and the build-up of abnormal amyloid proteins in Alzheimer brains, they found that certain variants of the gene were linked to an increased build-up of amyloid in blood vessels. The same variants were also associated with an increased production of TGF-beta1. These results suggest that inheriting TGF-beta1 genes that produce high levels of TGF-beta1 may put people at risk for accumulating in their cerebral blood vessels detrimental proteins that contribute to the development of Alzheimer’s disease.
To arrange interviews with Gladstone scientists, contact Corinna Kaarlela in the UCSF News Office at 415/476-3804.
For more information about World Alzheimer Congress 2000, contact the Congress press room at the Washington Hilton and Towers at 202-483-3000.