SBIR-STTR Award

Neuropathologic features of AD include neuritic amyloid plaques and tangles in cerebrocortical pathways in the brain. Recent studies have also shown that a heterogenous mixture of GAGs improves cognition in aged rats, and reversed cognitive and neurochemical deficits in patients with AD. Thus, GAGs may be potentially useful in the prevention of AD neuropathology. These Phase I studies will involve a preliminary screen of three new, specific GAGs. They will be tested in an animal model in which astrocytosis and trans-synaptic cytoskeletal and astrogliotic reactions similar to those seen in the AD patient are induced by injection of Abeta 25-35 into the rat amygdala. The GAGs' ability to prevent: (a) aggregation of Abeta; (b) production of abnormal tau immunoreactivity, reactive astrocytosis, and neuronal shrinkage; (c) changes in choline acetyltransferase, cholinesterase, serotonin, and 5HIAA levels; and (d) changes in the size of dendritic arbors and density of dendritic spines of neurons, using Golgi morphometry; will be explored in several brain regions. The objectives of this study are to identify and test prototypic homogenous GAGs that have potential for treatment of AD. PROPOSED COMMERCIAL APPLICATION: Development of a treatment for senile dementia of the Alzheimer type.

Thesaurus Terms:
Alzheimer's disease, brain disorder chemotherapy, drug screening /evaluation, mucopolysaccharide neurochemistry, neuropharmacology laboratory rat

The long-term objective of this proposal is to find novel treatment strategies in Alzheimer's disease. Phase I of this Small Business Technology Transfer application focused on C3, an ultra low molecular weight product of fractionated heparin. C3, a glycosaminoglycan (GAG), is composed mainly of 4-10 oligosaccharides, and has an appalent molecular weight of 1,940 and a USP value of 12 U/mg. In F344 rats C3 was shown to cross the blood brain barrier. It also prevented tau-2 immunoreactivity and astrocytosis (comparable to the type of neurodegeneration observed in Alzheimer's disease) that had been induced by injection of Abeta(25-35), directly into the amygdala in the brain of rats. C3 also increased the arborization of dendrites in the hippocampus; hence it may have neurotrophic activity in the brain. C3, and/or other, related GAGs, may therefore be effective as adjuncts in the treatment of Alzheimer type degeneration. Studies in this Phase II application will screen C3, as well as four related. ultra low molea about lar weight GAGs in the ~ 2000 molecular weight range. They will be subjected to a variely of tests in F344 male rats, aimed at selecting the best candidates for potential commercial application. Specific Aim 1 will establish the blood brain barrier permeability of these compounds, to exclude those that have a low penetrability into the brain. Specific Aim 2 will characterize the bleeding and thrombocytopenic potential of the remaining compounds, to exclude those that should not be used chronically in patients. Specific Aim 3 will measure the ability of the remaining GAGs to prevent tau-2 immunoreactivity and astrocytosis in brains following Abeta (25-35) injection into the amygdale of rats. Employing Golgi methodology, Specific Aim 4 will analyze the effect of the success about l GAGs on hippocampal dendritic morphometry, in young and aged rats, with and without their prior exposure to Abeta (25-35). Specific Aim 5 will evaluate attenuation and/or reversal of behavioral dysfunction in aged rats by the GAGs, using the open field, two-way conditioned avoidanee response, and Morris Water Maze tests. Brain cholinergic function will be assessed in these rats at the completion of the behavioral tests. Finally, Specific Aim 6 will establish the pharmacokinetic and pharmacodynamic profile of the selected GAGs. These studies should yield one, or possibly more, promising candidate(s) for subsequent extensive toxicological studies, followed by early clinical development. PROPOSED COMMERCIAL APPLICATION: This research introduces a new strategy to identify, screen and synthesize homogeneous glycosaminoglycans, which could ultimately be tested in clinical trials in patients with Alzheimer's Disease. the potential commercial outcome of these studies would be the development of new, effective agents for the prevention and/or treatment of Alzheimer's Disease.

Thesaurus Terms:
Alzheimer's disease, brain disorder chemotherapy, drug screening /evaluation, mucopolysaccharide, neuropharmacologic agent blood brain barrier, drug design /synthesis /production, neurochemistry, neuropharmacology, pharmacokinetics, tau protein, thrombocytopenia immunocytochemistry, laboratory rat