Proteoglycans/Glycosaminoglycans in APP Transgenic Mice

Award Information
Department of Health and Human Services
Award Year:
Phase I
Agency Tracking Number:
Solicitation Year:
Solicitation Topic Code:
Solicitation Number:
Small Business Information
12026 115TH AVE N.E., KIRKLAND, WA, 98034
Hubzone Owned:
Minority Owned:
Woman Owned:
Principal Investigator:
(425) 823-6364
Business Contact:
(425) 823-0400
Research Institution:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a degenerative brain disorders characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly, today affecting 4-5 million Americans, which is expected to double in incidence in the next 25 years. AD is characterized by the accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (Abeta), either as extracellular amyloid plaques in the brain parenchyma or in blood vessel walls. Abeta amyloid formation, deposition and persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction, and therefore has become a central target for the development of new drugs for the treatment of AD and related disorders. In AD, there is currently no cure or substantially effective treatment, and the patient usually dies within 3-10 years from disease onset. One of the most important amyloid co-components believed to play a primary role in the pathoqenesis of AD and other amyloid diseases are specific proteoqlycans (PGs) and glycosamino-qlycans (GAGs), especially those of the heparan sulfate (HS) class. Studies indicate that specific HSPGs accumulate early in AD brain and contribute to the pathoqenesis of Abeta amyloid formation by enhancinq Abeta deposition and persistence in brain. In both Down's syndrome and systemic AA amyIoidosis, it has been clearly demonstrated that HSPG formation and accumulation is an early event, prior to any detection of amyIoid (Abeta or AA amyIoid) deposition in tissues. Similarities between humans and mice with regards to the presence of specific HSPGs (including perlecan, aqrin, qlypican) in brain amyloid deposits make the APP transqenic mouse model a valuable tool to assess changes in HSPG deposition in brain and bioloqical fluids during initial and progressive phases of Abeta amyloid deposition and accumulation. Our data demonstrates that mice in general contain similar classes of GAGs in their plasma to their human counterparts (i.e. chondroitin-4-sulfate and heparan sulfate). In addition, our pilot data demonstrates that HS GAGs are elevated in CSF in AD versus normal aged controls, correlating with HSPG accumulation in AD brain. In this Phase I SBIR project we take advantage of important parallels between the APP transgenic mouse model and human AD (both in brain and biological fluids) to: 1) Identify the Specific HSPGs Upre, qulated in APP Transgenic Mouse Brain During Initiating and Progressive Phases of HSPG/Abeta Amyloid Deposition, and 2) Detect and Quantify Heparan Sulfate GAGs Derived from Biological Fluids of Human AD Patients and APP Transgenic Mice, and Determine Their Utility as a Diagnostic Marker for AD. These studies will lead to the identification and characterization of specific HSPGs/GAGs that are believed to play an early role in A( amyloid accumulation in AD and related disorders. In a future Phase II proposal, we intend to utilize important data generated from this Phase I project to isolate, fully characterize and prove that particular HSPGs in AD brain accelerate Abeta fibril formation and protect Abeta fibrils from protease degradation. We also intend to implement studies to prove that such an HSPG(s) is a relevant target for potential therapeutic intervention by testing a number of proprietary compounds developed at ProteoTech that block HSPG-Abeta interactions. In addition, we will more fully explore the use of plasma and CSF HS GAGs as diagnostic indicators of AD and its progression. It is clear from these projects that important commercial products (i.e. therapeutics and diagnostic) are anticipated to be developed for the treatment of AD and related disorders.

* information listed above is at the time of submission.

Agency Micro-sites

SBA logo

Department of Agriculture logo

Department of Commerce logo

Department of Defense logo

Department of Education logo

Department of Energy logo

Department of Health and Human Services logo

Department of Homeland Security logo

Department of Transportation logo

Enviromental Protection Agency logo

National Aeronautics and Space Administration logo

National Science Foundation logo
US Flag An Official Website of the United States Government