Hyaluronan-carnosine conjugates inhibit Aβ aggregation and toxicity.

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) is a leading cause of neurodegeneration, posing a significant research challenge.
• The amyloid cascade hypothesis implicates amyloid-beta (Aβ) oligomers as key toxic species in AD pathogenesis.
• Developing multi-target ligands and exploring endogenous compounds offers promising therapeutic avenues.

Purpose of the Study:

• To synthesize and characterize novel hyaluronic acid (Hy) derivatives functionalized with carnosine (Car).
• To evaluate the anti-amyloidogenic and neuroprotective potential of these HyCar compounds against Aβ aggregation and toxicity.
• To investigate the impact of HyCar on Aβ fibril degradation and enzymatic breakdown.

Main Methods:

• Synthesis and structural characterization of hyaluronic acid (200 and 700 kDa) conjugated with carnosine.
• In vitro assessment of Aβ42 anti-aggregation activity of HyCar derivatives.
• Evaluation of HyCar's ability to dissolve pre-formed amyloid fibrils.
• In vitro testing of Aβ-induced cytotoxicity reduction and impact on Aβ enzymatic degradation.

Main Results:

• Synthesized HyCar derivatives demonstrated superior inhibition of Aβ42 amyloid-type aggregate formation compared to parent compounds.
• Anti-aggregation efficacy correlated positively with carnosine loading.
• HyCar compounds effectively dissolved existing amyloid fibrils and reduced Aβ-induced cellular toxicity in vitro.
• Interaction with HyCar influenced the enzymatic degradation of Aβ.

Conclusions:

• Hyaluronic acid-carnosine conjugates (HyCar) represent a novel class of bioactive substances with significant anti-amyloidogenic properties.
• HyCar derivatives offer a promising multi-target approach for combating Alzheimer's disease by inhibiting aggregation and reducing toxicity.
• These findings support the investigation of endogenous compound derivatives as potential therapeutic agents for neurodegenerative disorders.