By Charles Glabe, Ph.D. University of California at Irvine
Professor, Molecular Biology and Biochemistry, School of Biological Sciences.
The current treatments for AD target the disease symptoms and to prevent or cure AD, new treatments are needed that target the causes of the disease. Aß oligomers are a leading candidate for causing AD, so it makes sense to develop strategies to prevent their formation, promote their elimination or inhibit their toxic activity.
Alzheimer’s disease (AD) is the most wide spread and debilitating disease that robs otherwise healthy individuals of essential functions, such as memory and cognitive ability. One of the critical aspects of AD is accumulation of misfolded proteins as deposits in regions of the brain involved in learning and memory that are known by the general term “amyloid”. One of the curious aspects of amyloid is that it also accumulates in other degenerative diseases associated with aging, like Parkinson’s and Huntington’s diseases and type II diabetes. In AD, the amyloid deposits are primarily made up of a small protein known as “amyloid beta”, or Aß, while in other degenerative diseases a different type of protein forms the amyloid. In most of these diseases, mutations in the amyloid forming protein promote the misfolding of the protein and are associated with rare inherited forms of disease, providing strong evidence that amyloid formation is closely linked to the disease.
Amyloids grow into long, thin fibrils by the addition of misfolded proteins on to the ends much like the addition of a single Lego block on to a stack. Proteins are linear strands of amino acids that fold into complex globular shapes that are critical for the proteins function. In order for a normal protein to form an amyloid fibril, it must undergo a change in its original shape from a globular form to an unwound abnormal shape that allows it’s self-assembly with other misfolded protein strands like Lego blocks. This assembly can go on infinitely, so that each amyloid fibril may contain a million or more individual subunits or blocks.
Although amyloid accumulation is a key feature of AD, it also presented an enigma because the accumulation of insoluble amyloid fibril deposits is poorly correlated with dementia. Some cognitively normal individuals were found to have the same amount of insoluble amyloid deposits as AD patients, indicating that these deposits are not always associated with disease. Similarly, other AD patients have been observed with relatively little of the insoluble amyloid deposits. These observations refocused research away from the insoluble amyloid deposits to other types of amyloid aggregates known as “oligomers”. More recent research in amyloid aggregation has discovered that the amyloid formation pathway also includes smaller aggregates, or oligomers and these oligomers have a different shape or conformation of the protein than that found in amyloid fibrils. Like Duplo blocks and Lego blocks, the oligomer conformation does not co-assemble with the fibril building blocks, but rather only supports the self-assembly of small aggregates of about 3-24 individual peptide strands. Amyloid oligomers have been observed for AD and other amyloid-related degenerative diseases. There is increasing evidence that these small oligomers, rather than the long fibrils, are the primary toxic or pathogenic species that cause all of these degenerative diseases. Oligomers are more toxic to cells and their presence correlates better with disease than the fibrils. Determination of the structures of these toxic oligomers, what they do to cause disease and how we may prevent their toxic activity are the primary objectives of Cure Alzheimer’s Fund Research Consortium Collaborative.
The Cure Alzheimer’s Fund Research Consortium Collaborative consists of five of the members of the Research Consortium and a member of the Cure Alzheimer’s Fund Science Advisory Board. This highly innovative collaborative project investigates critical aspects of amyloid oligomers in AD. The project is in it’s second year of funding.
For a full summary of the funded researchers and their projects, please visit our website www.curealzfund.org and see the
The laboratories of Dr. Charles Glabe, University of California at Irvine, and Dr. Virginia Lee, University of Pennsylvania, are making monoclonal antibodies that specifically recognize distinct types of amyloid oligomers. These properties of specific antibodies are very important for the development of passive immunotherapy and vaccines for AD, which is one of the leading strategies for therapeutic development (see “A Vaccine for Alzheimer’s disease?” by Dr. David Holtzman in the Fall 2006 quarterly report for more details about vaccine development.) Oligomer specific monoclonal antibodies are also useful for screening for drugs that prevent oligomer formation and as diagnostic agents. Although diagnostic agents may not seem to have much utility until better treatments are available for AD, they are critical for developing new therapies by allowing clinicians to recruit more homogeneous populations of individuals at risk for disease onset for human clinical trials. They are also crucial for drug development by allowing pharmaceutical companies to directly evaluate the effectiveness of drugs that target amyloid oligomers.
Drs. Rudy Tanzi and Robert Moir of Massachusetts General Hospital/Harvard Medical School are working on the discovery of drugs that prevent the formation of a novel type of amyloid oligomer knows as “cross-linked amyloid protein species” (CAPS). These results suggest that immunization with anti-CAPS antibodies and drugs that prevent the formation of CAPS might provide therapeutic benefit for AD. Drs. Tanzi and Moir are also providing CAPS to other members of the Cure Alzheimer Fund research consortium for analysis of their immunological properties and toxic activity.
Drs. Sangram Sisodia, University of Chicago, and Sam Gandy of Mt. Sinai Medical School are working on amyloid oligomers in transgenic mouse models of AD. Dr. Sisodia’s laboratory is working on Aß*56, a particular type of amyloid oligomer that is closely associated with the development of cognitive dysfunction in Tg2576 mice. Dr. Sisodia’s lab focuses on the molecular analysis of Aß*56 structure and function and how exercise may impact the formation of Aß oligomers. Dr. Gandy’s laboratory is developing new transgenic mouse models of AD that have different types of amyloid oligomers and these animal models will be shared with other members of the consortium. These animal models are very important for development of new therapeutics because they provide a means of determining the pathological significance of amyloid oligomers and they can be used for testing new drugs and vaccines for effectiveness.
Drs. Paul Greengard of The Rockefeller University, David Holtzman of Washington University at St. Louis and Dr. Tae-Wan Kim of Columbia University Medical Center are investigating the relationship between oligomers and neuronal synapse function. Synapses are critical for neuronal communication in learning and memory and there is evidence that synaptic loss and dysfunction play a role in AD.
Why target Aß oligomers?
The current treatments for AD target the disease symptoms and to prevent or cure AD, new treatments are needed that target the causes of the disease. Aß oligomers are a leading candidate for causing AD, so it makes sense to develop strategies to prevent their formation, promote their elimination or inhibit their toxic activity. Vaccination against Aß has shown considerable promise in human clinical trials, but one of the hurdles that must be overcome in order to develop an effective vaccine is to develop vaccines that lack undesirable inflammatory side effects. Vaccines that specifically target the misfolded conformation specific to amyloid oligomers may eliminate oligomers or block their toxicity and overcome these side effects. Since the structures recognized by the antibodies are specific for the disease state and do not recognize the normal, non-disease related protein structures, vaccination against the oligomeric conformation may be less likely to cause inflammatory complications. Conformation dependent monoclonal antibodies may be more effective therapeutic agents because they bind only to the pathological oligomers that are present at low concentrations and will not bind to amyloid plaques. Similarly, drugs that specifically target Aß oligomer formation or toxicity may be more effective because lower concentrations of drugs may be needed to achieve a therapeutic benefit and they may have lower side effects as a consequence. The Cure Alzheimer’s Fund Research Consortium Collaborative has a broad and integrated research program that is focused on developing therapeutic agents that prevent or cure AD by targeting the cause of AD.