Polyampholyte-Based Synthetic Chaperone Modulate Amyloid Aggregation and Lithium Delivery.

Protein misfolding and aggregation is the pathological hallmark of Alzheimer's disease (AD). The etiopathogenesis of AD involves the accumulation of amyloid-β (Aβ) plaques in the brain, which disrupt the neuronal network and communication, causing neuronal death and severe cognitive impairment. Modulation of Aβ aggregation by exogenous therapeutic agents is considered an effective strategy to treat AD. Frequent failure of drug candidates in various phases of clinical trials reiterates the need for alternative therapeutic strategies for AD treatment. Polyampholytes with cationic and anionic segments are considered as artificial protein mimics capable of modulating the protein misfolding and aggregation. We report a diblock copolymer of tryptophan-functionalized methacrylic acid (PTMA) polyampholyte synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization. Investigation revealed that PTMA acts as a synthetic chaperone to protect the native structure of the lysozyme under heat-induced aggregation conditions. PTMA effectively modulates Aβ aggregation and rescues neuronal cells. Lithium has been shown to exhibit therapeutic efficacy in chronic neurological diseases including AD. PTMA sequesters and releases lithium ions in response to neuropathological pH stimuli, making it a promising candidate for lithium transport and delivery. The detailed studies demonstrate PTMA as aggregation modulator and lithium carrier with implications for combinational therapy to treat AD.