Research Project
6626015
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a degenerative brain disorder 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 American, which is expected to double in incidence in the next 25 years. AD is characterized by the brain 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. AB 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 years of disease onset. Our Phase I SBIR studies demonstrated that the basement membrane protein laminin acts as a potent inhibitor of AB fibril formation, both in vitro and in vivo. Following elastase digestion and sequencing, an AB-binding site on laminin was localized to the C-terminal globular domain repeats on the laminin Al chain, within a 55-kDa region. A 12 amino acid peptide was futher identified within the 4th globular domain of laminin Al to be a potent inhibitor of ABeta fibrillogenesis. Following the screening of over 300 overlapping 12-14 amino acid peptides of various laminin alpha-chain globular domains, we identified six ideal peptide candidates (each 12-13 amino acids in length) that were found to be potent inhibitors of ABeta amyloid fibril formation, and which cause a disruption of pre-formed AD amyloid fibrils. Based on these promising results, Phase II SBIR studies will involve the synthesis of related peptide analogs (i.e. D-amino acids, smaller truncated peptides) derived from the six parent form laminin globular domain-derived peptides with the goal of optimizing new peptides that have the ability to 1) inhibit All fibril formation and disrupt/disassemble preformed All fibrils, 2) inhibit All-induced toxicity, 3) resist rapid bio-degradation, 4) cross the blood-brain barrier, and 5) retard or reverse AD-like amyloid plaque pathology in a transgenic mouse model of AD. These studies are anticipated to lead to the identification of a new peptide candidate for the treatment of All amyloidosis in AD and related disorders.
