Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgement 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 within the next 25 years. AD is characterized by the accumulation of insoluble fibrillar amyloid deposits in brain containing the beta-amyloid protein (Abeta), either as extracellular amyloid plaques or in walls of blood vessels in the brain parenchyma. Abeta amyloid persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction. There is currently no cure or effective treatment for AD, and the patient usually dies within 3-10 years from disease onset. Our preliminary studies demonstrate that laminin and laminin fragments may serve as potent inhibitors of Abeta fibrillogenesis. We have identified a specific region within laminin (i.e. the globular domains of the laminin A chain) which binds Abeta and may be responsible for the observed amyloid inhibitory effects of intact laminin. The major objectives of this Phase I SBIR proposal are to 1) determine whether the globular domains on the laminin A chain (i.e. approximately 55 kDa region) or fragments thereof are responsible for the Abeta amyloid inhibitory effects initially observed with intact laminin, and 2) determine if such specific laminin fragments may serve as inhibitors of Abeta amyloidosis in vitro and in vivo. These studies are anticipated to lead to new possible treatments for brain Abeta amyloidosis, believed to contribute to the neuropathology and clinical manifestations of AD. Identification of Abeta amyloid inhibitory fragments of laminin is also expected to lead to new drug design for anti-amyloid therapeutics for the future.
Alzheimer's disease (AD) currently affects 4-5 million Americans, at an estimated cost of $80-$100 billion. Currently, there is no cure or effective treatment, and the patient usually dies within 3-10 years after the disease onset. Identification of new proteins or peptides capable of influencing and reducing Abeta amyloidogenesis may serve as potential new therapeutics for the future.
| Castillo, G M; Lukito, W; Peskind, E et al. (2000) Laminin inhibition of beta-amyloid protein (Abeta) fibrillogenesis and identification of an Abeta binding site localized to the globular domain repeats on the laminin a chain. J Neurosci Res 62:451-62 |
