Current Strategies for Modulating Aβ Aggregation with Multifunctional Agents.

Abstract

Alzheimer's disease (AD), as the primary cause of dementia, has seriously affected millions of people worldwide and brought a very heavy financial and social burden. With the growth of population and aging, the situation will worsen unless efficacious drugs are found to reverse, stop, or even slow down disease progression. More and more evidence has demonstrated that amyloid-β (Aβ) aggregation is an upstream causative factor in AD pathogenesis and then triggers a slew of pathological events. Furthermore, the concentrated redox metal ions in the AD brain, especially Cu(II), can significantly exacerbate Aβ aggregation and contribute to the formation of neurotoxic reactive oxygen species (ROS). Therefore, the inhibition of Aβ aggregation and relief of amyloidosis-initiated neurotoxicity play a critical role in AD treatment. Until now, several methods have been proposed to modulate Aβ aggregation, such as developing aggregation inhibitors to interfere with Aβ assembly via noncovalent interactions, copper chelators to cut off metal-accelerated Aβ aggregation and concomitant cytotoxicity, photooxidation to reduce the hydrophobicity and aggregation tendency of Aβ, thermal dissociation to disrupt amyloid aggregates susceptible to temperature, degradation with artificial protease to fracture the Aβ peptide into small fragments, and the clearance of peripheral Aβ to bypass the obstruction of the BBB and reduce the Aβ burden.In this Account, we focus on our contributions to the development of Aβ-targeted multifunctional molecules and nanoparticles, emphasizing the diversified strategies and synergistic therapeutic effects. These therapeutic agents possess the following multifunctionalities: (1) compared with frequently used aggregation inhibitors restricted by intrinsically feeble and sensitive noncovalent interactions, multifunctional agents can efficiently block Aβ aggregation by exploiting two or more Aβ-specific inhibition strategies simultaneously; (2) apart from regulating Aβ aggregation, multipronged agents can also target and modulate other pathological factors in AD pathogenesis, such as increased oxidative stress, abnormal copper accumulation, and irreversible neuron loss; (3) multifunctional platforms with both diagnostic and therapeutic modalities through integrating in situ imaging, real-time diagnostics, a multitarget direction, stimuli-responsive drug release, and the blood-brain barrier (BBB) translocation features are instrumental in improving drug levels at trouble sites, diminishing off-target adverse reactions, evaluating therapeutic effects, and averting overtreatment.Given the fact that amyloid aggregation, local inflammation, and metal dyshomeostasis are universal biomarkers shared by various neurodegenerative disorders, this Account provides a perspective for the evolution of customized therapeutic agents with multiple reactivities for other neurodegenerative diseases. In addition, recent studies have indicated that Aβ aggregates can enter the nucleus and induce DNA damage and anomalous conformational transition. We also explore the influences of DNA on the biological effects of Aβ aggregates.