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

Abstract

Alzheimer's disease (AD) is a major neurodegenerative disorder and the leading cause of dementia worldwide. Predominantly, misfolding and aggregation of amyloid-β (Aβ) peptides associated with multifaceted toxicity is the neuropathological hallmark of AD pathogenesis and thus, primary therapeutic target to ameliorate neuronal toxicity and cognitive deficits. Herein, we report the design, synthesis and evaluation of small molecule inhibitors with naphthalene monoimide scaffold to ameliorate in vitro and in vivo amyloid induced neurotoxicity. The detailed studies established TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. The in silico studies showed disruption of salt bridges and intermolecular hydrogen bonding interactions within Aβ42 fibrils by the interaction of TGR63, causing destabilization of Aβ42 assembly. Remarkably, TGR63 treatment showed a significant reduction in cortical and hippocampal amyloid burden in the progressive stages of APP/PS1 AD mice brain. Various behavioral tests demonstrated rescued cognitive deficits. The excellent biocompatibility, BBB permeability and therapeutic efficacy to reduce amyloid burden make TGR63 a promising candidate for the treatment of AD.

Carnosic acid ameliorated Aβ-mediated (amyloid-β peptide) toxicity, cholinergic dysfunction and mitochondrial defect in Caenorhabditis elegans of Alzheimer's Model

“…The abnormal accumulation of Aβ in brains destroys neurons, which eventually leads to synaptic dysfunction and cognitive disorders associated with AD. 43,44 Strain CL2355 expresses…”

Combating amyloid-induced cellular toxicity and stiffness by designer peptidomimetics

“…Natural peptide-based amyloid inhibitors offer numerous advantages over small molecule inhibitors [18][19][20][21] owing to their biological origin, biocompatibility, target-specific binding, sequence variability and ease of synthesis. [22][23][24][25][26][27][28][29] Short peptides with 16 KLVFF 20 derived from Ab42 have been shown to inhibit Ab aggregation.…”

Trilobatin Alleviates Cognitive Deficits and Pathologies in an Alzheimer’s Disease Mouse Model

“…However, drugs that target Aβ deposition or Tau phosphorylation would not efficiently halt AD progression in recent years [5,6]. Besides synthetic drugs, many traditional Chinese medicines and natural products are found available for AD management [7][8][9][10][11][12]. These research studies shed new light on the discovery of natural products to alleviate AD pathologies.…”