Funded Programs Drug Discovery

Role of leukocyte adhesion in impaired cerebral blood flow in Alzheimer\'s disease.

Summary:
Cerebral blood flow decreases of about 30% have been noted in both humans with Alzheimer\'s disease (AD) as well as in mouse models of AD, and may play a role in cognitive impairment. The underlying mechanism for this decrease in cerebral blood flow has not yet been elucidated. In recent work, we have discovered that there is an approximately six-fold elevation, from 0.3 % to 1.8%, in the number of brain capillaries that are stalled in aged AD mice as compared to age-matched controls. In previous work, we also quantified the downstream blood flow decreases that result from the occlusion of a single cortical capillary. Based on this data, we predict that the increase in capillary stalls we have observed in AD mice would lead to an overall 30% decrease in cerebral perfusion, suggesting that the decreased cerebral blood flow in AD could be caused by stalled flow in brain capillaries. In preliminary data, we have further linked these stalls to leukocytes that are firmly adhered to the endothelium of capillaries. Many studies have noted an increase in inflammation in the AD brain, which could cause activation of endothelial cells and lead to such leukocyte plugging. Here, we propose to build on our preliminary data and confirm that leukocyte plugging causes the increased stalling of brain capillaries in AD mice. We then will block the interaction between leukocytes and inflamed endothelial cells using blocking antibodies and determine if this resolves the capillary stalls and leads to increased cerebral perfusion. Taken together, this work would definitively identify leukocyte plugging as a cause for the decreased brain blood flow seen in AD as well as determine how much cerebral blood flow could be increased by eliminating the leukocyte plugs, suggesting a novel therapeutic target for AD.

Behavioral efficacy testing of anti-Abeta 42 oligomer small molecules.

Summary:
Cognition Therapeutics Inc.'s mission is to discover disease-modifying drugs for Alzheimer's disease that block the toxic proteins that build up in the brains of these patients. Alzheimer's disease begins as Mild Cognitive Impairment, marked by a loss of memory. This memory loss is through to be caused by a buildup of these toxic proteins in the brain. Scientific evidence suggests that one of the first proteins to build up in the diseased brain is beta-amyloid. Individual beta-amyloid proteins begin to stick to each other and form a toxic shape known as an oligomer (from the Greek word for "many"). Unlike monomers, beta-amyloid oligomers are thought to bind to the surface of the neuron at synapses and interfere with synaptic communication, which leads to memory failure, the first sign of impending disease. Cognition's strategy to combat Alzheimer's disease is to find a small molecule drug that can stop beta-amyloid oligomers. Cognition is looking for these drugs by studying actual mature brain cells, or neurons, in the petri dish. These neurons and their support cells (known as glia) are allowed to grow for more than three weeks, during which time they form connections and communicate with each other as they do in the adult brain. Using these, cells Cognition discovered several novel related families of molecules that stop the toxic effects of oligomers. Initial tests on the drug-like properties of the compounds indicate that these molecules can survive in the blood stream for sufficient lengths of time to allow them to be tested in animal models. If effects in animal models continue to be promising, these molecules will then be engineered into drugs by an iterative process known as medicinal chemistry. These molecules represent some of the first ever reported to specifically target toxic beta-amyloid oligomers and stop their effects on neurons.

Tau oligomers for treatment of Alzheimer\'s Disease

Summary:
An emerging view is that neurofibrillary tangles (NFT) themselves are not the true toxic entity in Alzheimer`s (AD) and other tauopathies; rather, aggregates of a size intermediate between monomers and NFT- so-called tau oligomers- are pathogenic. Recently my laboratory developed novel polyclonal and monoclonal antibodies that recognize specifically oligomeric forms of tau. These novel reagents and methodologies we have developed should enable us for the first time to systematically assess the role of tau oligomers in AD and other tauopathies in patients and in animal models. The final aim of the proposal is to target tau oligomers in mouse models via a vaccine approach which I believe could yield a disease-modifying therapy for AD in the next 10-15 years.

Tau oligomers for treatment of Alzheimer\'s Disease

Summary:
Vaccination again proteins that accumulate in the disease has gained a great deal of momentum as a therapeutic approach to Alzheimer’s disease (AD). Although tau accumulation and tangles are a key pathological hallmark of AD, previous vaccination studies have been almost exclusively focused on Aβ peptide rather than on tau. Recently it has become clear from these studies that Aβ immunization, while demonstrating clearance of amyloid, causes many side effects and does not reduce tau pathology. Dr. Kayed has developed a novel antibody specific for the small aggregates of tau, called tau oligomers. Research indicates that such oligomeric tau species play a critical role in AD and other neurodegenerative disorders. With his previous year of ADDF funding, Dr. Kayed demonstrated that a single injection of the antibody is sufficient to reverse AD-related defects in mouse models. Tau immunotherapy is a relatively new concept. While there is much appeal, there are concerns that since tau is an endogenous protein with a normal cellular function, such efforts may induce autoimmunity and/or other complications. With this in mind, Dr. Kayed has developed a novel anti-tau oligomer specific antibody. This antibody does not recognize normal tau or mature tau tangles and has a high affinity to tau oligomers. The ultimate aim of this project is to develop a disease-modifying vaccine; over the next 3-5 years Dr. Kayed will focus on production and evaluation of the humanized antibody that will ultimately be tested in clinical trials.

Imaging agents for diagnosis of tauopathic neurodegenerative diseases

Summary:
This is a follow-on study to develop radiotracers for differentially diagnosing and staging Alzheimer\'s disease (AD) through whole brain imaging. Our strategy targets the neurofibrillary lesions composed of tau protein instead of beta-amyloid lesions because the former appear early in the course of disease and correlate well with neurodegeneration as disease progresses. For these reasons, assessment of neurofibrillary pathology is the current gold standard for post-mortem diagnosis and staging of AD. Our project seeks to port this approach to living people. Past support from ADDF/Elan Pharmaceuticals allowed us to conduct a preliminary characterization of binding sites on synthetic tau aggregates, to prepare a new mathematical model of radiotracer pharmacokinetics capable of guiding the discovery process, and to complete a preliminary structure activity relationship for benzothiazole-aryl and oxindole derivatives. Most importantly, it allowed us to address the issue of relative binding selectivity for aggregates composed of tau over beta-amyloid, which is the crucial roadblock that must be overcome in the development of tau-based radiotracers. Results from these studies indicate that synthetic tau aggregates have a greater tolerance for certain ligand substituents relative to beta-amyloid aggregates, and therefore that tau selectivity can be generated by \"dialing down\" affinity for beta-amyloid. The goal of the current application is to extend these results to radiotracer concentrations, and to build a quantitative structure activity relationship suitable for lead optimization. Successfully completed, this study will reveal the final affinity and selectivity characteristics needed for success, and take us to the key go/no-go decision point of whether to initiate lead optimization. Over the long-term, when combined with emerging therapies for AD, direct premortem detection of tau aggregates has the potential to change the standard of care for this deadly disease.