MT1-MMP-MODIFIED POLYDOPAMINE NANOPARTICLES FOR THE POTENTIAL TREATMENT OF ALZHEIMER`S DISEASE

Alzheimer`s disease (AD) is characterized by progressive deterioration in cognition and memory. The etiology of AD is believed to be related to the formation and deposition of plaques and neurofibrilar tangles that are composed of tightly aggregated fibrilar amyloid-beta (Aβ) and hyper-phosphorilated Tau proteins, respectively (1). Based on amyloid hypothesis AD is caused by an imbalance between Aβ production and clearance (2) resulting in increased amounts of Aβ aggregates in central nervous system. The high levels of Ab species can then initiate a cascade of events that lead to neuronal damage and death manifesting as progressive clinical dementia in AD (3). In this study, we present a new approach for the clearance of Aβ species, which is based on polydopamine (PDA) nanoparticles modified by the catalytic domain of the membrane type-1 matrix metalloproteinase (MT1-MMP) that is known for its enzymatic activity to cleave of Aβ. The enzymatic activity of PDA-conjugated MT1-MMP was confirmed by HPLC and mass spectrometry, while FACS, TEM and Thioflavin T assay (ThT) were used to study the interaction between Ab and PDA-conjugated MT1-MMP. These studies suggest that the naked PDA particles directly bind Aβ, most probably through p-p interactions, inhibit its aggregation and eliminate its cytotoxicity to PC-12 cells. We also shown that the immobilized MT1-MMP preserves the catalytic activity of the soluble enzyme to cleave Ab and thus exhibit significantly better anti-amyloidogenic activity than naked PDA. The immobilized MT1-MMP has lower toxicity to cells than naked PDA-nanoparticles and demonstrates higher stability than soluble enzyme.