Transthyretin, αAPP peptides and Alzheimer's Disease

Demographics point to increasing rates of Alhzheimer's Disease. This disease steals away the golden years of sufferers. It also costs society billions healthcare.

Research for the cure marches on. Researchers know the disease is characterizedby the deposition of amyloid β-peptide (A-Beta) in the brain. The challenge is finding a way to protect the brain from these depositions or reverse the process.

Dr. Isabel Cardoso and her team at Instituto de Biologia Molecular e Celular have recently published compelling work in this area. Here they provide more important evidence for the role of a Transthyretin (TTR) protective mechanism. This mechanism could include the removal of deposited A-Beta.

Rita Costa, Frederico Ferreira-da-Silva, Maria J. Saraiva, and Isabel Cardos. Transthyretin Protects against A-Beta Peptide Toxicity by Proteolytic Cleavage of the Peptide: A Mechanism Sensitive to the Kunitz Protease Inhibitor.
PLoS ONE. 2008; 3(8): e2899. Published online 2008 August 6. doi: 10.1371/journal.pone.0002899.

A-Beta proteolysis by TTR is KPI-sensitive.
A- A-Beta incubated with TTR (A-Beta+TTR) shows a weaker A-Beta monomer band as compared to A-Beta alone (A-Beta), indicative of proteolysis, as analyzed by SDS-PAGE electrophoresis followed by western blot. Pre-incubation of TTR with pefabloc (A-Beta+(TTR+pefabloc)) and with an αAPP peptide containing the KPI domain (A-Beta+(TTR+KPI+−APP)) inhibits TTR proteolytic activity, whereas the αAPP peptide without the KPI domain (A-Beta+(TTR+KPI−−APP)) facilitates proteolysis. B- % of inhibition of TTR proteolysis by quantification of band intensity in A. C- Ultrastructural analysis by TEM of preparations incubated for 15 hours, as described in Materials and Methods. TTR inhibited A-Beta aggregation as compared with A-Beta incubated alone (upper panels). Pre-incubation of TTR with αAPP peptide containing the KPI domain (A-Beta+(TTR+KPI+−APP)) abrogated TTR ability to avoid A-Beta aggregation, whereas αAPP lacking the KPI domain (A-Beta+(TTR+KPI−−APP)) did not affected TTR activity (lower panels). Scale bar=500 nm.

Neuromics' Reagent Used-APP 228