AIzheimer's disease (AD) is a progressive amnestic disorder that involves the post-translational hyperphosphorylation, enzymatic cleavage, and deposition of the microtubule-associated protein, tau, to form neurofibrillary tangles. Early in tangle evolution, C-terminal cleavage of 20 amino acids by caspase-3 results in a protein with accelerated self-assembly. While N-terminal truncation has been proposed as a mechanism for tau's loss of binding to some antibodies with epitopes in the extreme N-terminus, a specific truncation site has yet to be identified in vivo. It is likely that such a truncation would affect filament assembly, stability and toxicity. Furthermore, N-terminal cleavage would remove a portion of the AIz-50 conformation-dependent epitope (a marker of early tangle formation) and may thereby increase the amount of tau in the Tau-66 (advanced tangle) conformational epitope. In this proposal, a panel of existing N-terminal antibodies and mass spectrometry will be used to uncover the exact location of the N-terminal cleavage(s) in AD brains, and the effects of truncations on tau behavior will be studied. N-terminal truncation-specific antibodies will also be generated to aid in the study of this important event in Alzheimer's disease progression.
| Horowitz, Peleg M; LaPointe, Nichole; Guillozet-Bongaarts, Angela L et al. (2006) N-terminal fragments of tau inhibit full-length tau polymerization in vitro. Biochemistry 45:12859-66 |
| Sengupta, Soma; Horowitz, Peleg M; Karsten, Stanislav L et al. (2006) Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro. Biochemistry 45:15111-9 |
