Alzheimer's Disease: The role of alpha1-antichymotrypsin-amyloid peptide (Abeta 1-42) interaction in the pathogenesis of Alzheimer's disease

Alzheimer’s disease (AD) is an age-related, irreversible brain disorder that occurs gradually and results in memory loss, behavioural and personality changes. The disease is characterized by an abnormal accumulation of amyloid-beta (Ab) peptide in the extracellular space and the protein Tau within nerve cells of certain regions of the brain. Aâ1-42 is a major component of amyloid deposits in AD, but other molecules related to inflammation, such as proteases and their inhibitors, proteoglycans, cytokines and extracellular matrix proteins, are also co-localized. In addition, the activated glia is shown to surround the amyloid core, indicating the presence of inflammation in AD brains. á1-antichymotrypsin (ACT) is an acute phase reactant that belongs to the family of serine protease inhibitors and is specifically found to interact with Aâ1-42 and be present in amyloid deposits in AD brain. We studied the interaction between Aâ1-42 and ACT, and the biological activities of Aâ1-42/ACT complex mixture on cellular lipid metabolism, cytokine release and expression of nuclear transcription factors, in vitro. Our data show that the Aâ1-42/ACT complex mixture induces more profound intracellular accumulation of native and oxidised LDL in human neuroblastoma (Kelly) cells and stimulates a larger release of TNFá in human glioma (DK-MG) cells, compared to Aâ1-42 peptide alone. Moreover, Aâ1-42/ACT complex mixture was found to activate more strongly inflammation-related transcription factors peroxisome proliferator-activated receptor-ã and nuclear factor-êB than Aâ1-42. Findings that pre-treatment of glioma cells with pravastatin diminished or totally suppressed the capacity of soluble Ab1-42 to induce gelatinase B, interleukin-6 and free radical generation allowed us to propose that, the observed effects of pravastatin may be what contribute to its beneficial anti-inflammatory properties described, in vivo. By analyzing biomarkers related to inflammation in plasma and matched cerebrospinal fluid (CSF) from patients with probable AD, we found a positive correlation between plasma and CSF levels of ACT, IL-6, MCP-1 and oxLDL, indicating that the plasma levels and certain combinations of these biomarkers may provide good possibilities to describe the disease status in Alzheimer’s patients. Our data support the hypothesis that the interactions between Aâ1-42 and ACT, or Aâ1-42 and other molecules present in amyloid deposits, may have an important effect on the chronic inflammatory process present in AD, in vivo, and could be used as markers to evaluate the progression of the disease.