Antioxidant Berberine-Derivative Inhibits Multifaceted Amyloid Toxicity

Abstract

Multiple lines of evidence indicate that amyloid beta (Ab) peptide is responsible for the pathological devastation caused in Alzheimer's disease (AD). Ab aggregation species predominantly contribute to multifaceted toxicity observed in neuronal cells including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity of AD. The structural attributes of polyphenolic Ber-D have contributed to its efficient Cu chelation and arresting the redox cycle to prevent the generation of ROS and rescue biomacromolecules from oxidative damage. Ber-D inhibits metal-dependent and -independent Ab aggregation, which is supported by in silico studies. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis. These key multifunctional attributes make Ber-D a potential therapeutic candidate to ameliorate multifaceted Ab toxicity in AD.

Prodromal Alzheimer’s Disease: Constitutive Upregulation of Neuroglobin Prevents the Initiation of Alzheimer’s Pathology

“…In order to obtain oligomers, the peptide was diluted to 100 µM in DMEM and after vortexing, it was incubated overnight at 4 • C. The state of aggregation of the peptide was verified by transmission electron microscopy. Due to the fact that B27 supplement contains antioxidants in its formulation, and antioxidants are known to inhibit Aβ-mediated toxicity (Ono et al, 2006;Manczak et al, 2010;Giordano et al, 2014;Rajasekhar et al, 2020), we replaced the media by Minimal Essential Medium (MEM) containing antioxidants-free N2 supplement, which has been previously used to study Aβ toxicity (Bateman et al, 2007;Uchida et al, 2011;Ungureanu et al, 2016). On DIV 8, the B27-supplemented medium was progressively replaced (1/4 of the media each day for 3 days, the 4th day being totally replaced) with MEM media supplemented with N2 (Gibco; Life Technologies Co.) and without GlutaMAX, and subsequently treated with oligomeric Aβ to study dendritic arborization (100 nM), mitochondrial respiration (10 µM) or Ngb expression (5 µM), at 8 DIV, 10 DIV or 14 DIV, respectively.…”

Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease

“…The soluble Aβ aggregation species, namely oligomers, are considered highly toxic and critical contributors to Aβ toxicity (5,8). Aβ oligomers are known to interact and disrupt the lipid membranes (mitochondrial and plasma membranes), causing mitochondrial dysfunction and neuronal damage (18). The disruption of the plasma membrane at synaptic cleft causes synaptic dysfunction, followed by weakening in synaptic plasticity and LTP formation (10)(11)(12)(13)(14).…”

“…S8). The calculated positive logP value predicts the possible BBB crossing ability for TGR63 (18). For in vivo assessment, TGR63 and vehicle administrated WT mice were sacrificed after 1 h to collect the brains for MALDI mass analysis.…”

“…Identification of potent small molecules to ameliorate Aβ burden and associated cognitive deficits eluded researchers and clinicians to find an effective treatment for AD (8). Targeting Aβ burden includes the modulating production, misfolding and parenchymal plaques deposition of Aβ, promotion of plaques clearance and amelioration of neuropathological hallmarks and cognitive decline (9,18,37). Inhibition of β or γ-secretases is a promising approach to reduce the Aβ production, albeit their expression and functional relevance in others part of the body failing a large number of clinical candidates due to severe side effects and off-target interactions (38).…”

“…The clinicopathologic studies correlate cognitive decline or sequence of AD pathology to Aβ burden associated toxicity in the AD brain (8,15,16). These facts and reports have underscored the importance of clearing or reducing the Aβ burden from the brain as a primary target to develop therapeutic agents for the treatment of AD (17)(18)(19). The amyloid toxicity emphasizes the need for a novel drug design strategy to ameliorate Aβ burden-associated plasma membrane toxicity, cognitive decline and memory (STM and LTP) impairment under progressive AD pathogenesis (20)(21)(22).…”