Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation

Abstract

Synergistic modulation of multifaceted toxicity is the key to tackle multifactorial Alzheimer’s disease (AD). The etiology of AD includes amyloid β (Aβ) amyloidosis, metal ion dyshomeostasis, reactive oxygen species (ROS), oxidative stress, mitochondrial damage, and neuroinflammation. We rationally designed multifunctional modulators by integrating pharmacophores for metal chelation, antioxidant and anti-inflammatory properties, and modulation of Aβ42 aggregation on the naphthalene monoimide (NMI) scaffold. The in vitro and cellular studies of NMIs revealed that M3 synergistically modulates metal-independent and -dependent amyloid toxicity, scavenges ROS, alleviates oxidative stress, and emulates Nrf2-mediated stress response in neuronal cells. M3 effectively reduced structural and functional damage of mitochondria, reduced Cyt c levels, and rescued cells from apoptosis. The biological atomic force microscopy and Western blot analysis revealed the ability of M3 to suppress microglial activation and neuroinflammation through inhibition of the NF-κβ pathway. The synergistic action of M3 is in agreement with our design strategy to develop a multifunctional therapeutic candidate by integrating multiple pharmacophores with distinct structural and functional elements to ameliorate the multifaceted toxicity of AD.

Cyclic dipeptide‐based small molecules modulate zinc‐mediated liquid–liquid phase separation of tau

“…We have rationally ensembled dipicolylamine (DPA), naphthalene monoamide (NMI), and CDP with aromatic functionalities to generate multivalent SMMs 1a ‐ c (Figure 1B and C). DPA is a known Zn chelator and possibly engages in charge–dipole and π–π interactions 48 . NMI engage in π–π and hydrophobic interactions, and potentially interrupt stearic zipper motifs interaction that drives aggregation 49 .…”

“…DPA is a known Zn chelator and possibly engages in charge-dipole and π-π interactions. 48 NMI engage in π-π and hydrophobic interactions, and potentially interrupt stearic zipper motifs interaction that drives aggregation. 49 The alkyl chain of CDP contributes to hydrophobic interactions, CDP-core with multiple hydrogen bonding ability increases valency of interactions, and imparts resistance to proteolytic degradation and bioactivity.…”

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

“…We recently reported a multifunctional small molecule M3 that effectively reduced microglial activation and neuroinflammation. 225 M3 effectively inhibits NF-κβ mediated neuroinflammation and reduces TNFα levels in Aβ activated microglial cells.…”

“…We developed multifunctional modulators by integrating NMI core with metal chelating dipicolylamine moiety and dopamine with antioxidant, and antiinflammatory properties. 225 Among the designed modulators, M3 with all three pharmacophore units effectively alleviate multifaceted Aβ toxicity (Fig. 13J).…”

Biodegradable Poly(trehalose) Nanoparticle for Preventing Amyloid Beta Aggregation and Related Neurotoxicity

“…With time, the aggregates interact with the cell membrane or enter inside cells and trigger intracellular pathogenesis (tauopathy, oxidative stress, and cytotoxicity) leading to neuronal loss. ,, Therefore, targeting and clearance of amyloid β are considered the main therapeutic strategy to combat AD. − Currently, approved drugs provide only symptomatic/temporary relief without affecting the core pathogenesis. − Recently, the Food and Drug Administration of USA (FDA) has approved aducanumab (monoclonal antibody sold under trade name “Aduhelm”) which represents a first-of-its kind treatment approved for AD. , It is the first therapy that targets the basic pathophysiology of the disease, and it is the first new treatment approved for AD since 2003 . Still, specific criticisms of the approval comprise the evidence of efficacy and very high cost. , Thus, research still strives for new medicines and new cost-effective strategies to target and degrade amyloid β aggregates. ,,,,− …”