| Alzheimer's disease is a neurodegenerative disorder that afflicts over 25 million people worldwide and currently has no cure. The amyloid β peptide (Aβ) is believed to be causative in the disease, but the exact form of the peptide responsible is unknown. The prevailing theory for Aβ toxicity is that innocuous monomer must reorganize into larger structures and form fibrils in order to be toxic. Recently, pre-fibrillar forms of the peptide have been discovered and are gaining in prominence as possible critical toxic structural species. We have discovered one of these pre-fibrillar forms of amyloid β and have named them, ADDLs (Amyloid-β-derived diffusible ligands). These structures are individual, globular, oligomeric species and are structurally distinct from other pre-fibrillar structures, such as rings, protofibrils, or micelles. We have designed several polyclonal antibodies to investigate these oligomers. Atomic force microscopy (AFM) and gel electrophoresis techniques have established the structure of the molecules. ADDLs have been demonstrated to block LTP, a model for learning and memory. It may be through this process that ADDLs exert their effect on the human brain and elicit the symptoms of AD. Moreover, the LTP and toxic effects of ADDLs are dependent upon the presence of Fyn, a Src-family tyrosine kinase, shown to be upregulated in AD. We have generated Fyn containing cell lines to examine the effects of Fyn more closely. Fyn has also been shown to phosphorylate tau, which is the main component of the other ‘hallmark’ of AD, the presence of paired helical filaments (PHFs) inside neurons of AD-afflicted brains. Although ADDLs have not been shown to conclusively elicit apoptosis, we have shown that perturbations in the microtubule network induce neuronal apoptosis through an unknown tyrosine kinase, possibly involving the Fyn-dependent signal transduction mechanism used by ADDLs. Apoptosis may play a role in how neurons die in AD, and disruption of the microtubule system through protein tyrosine phosphorylation may play a role in the apoptosis. ADDLs, Fyn, and protein tyrosine phosphorylation may represent central aspects of the cause of AD and further examination of these topics may eventually lead to a cure for this devastating disease. |
