The global burden of Alzheimer's disease (AD) is growing. Valiant efforts to develop clinical candidates for treatment have continuously met with failure. Currently available palliative treatments are temporary and there is a constant need to search for reliable disease pathways, biomarkers and drug targets for developing diagnostic and therapeutic tools to address the unmet medical needs of AD. Challenges in drug‐discovery efforts raise further questions about the strategies of current conventional diagnosis; drug design; and understanding of disease pathways, biomarkers and targets. In this context, post‐translational modifications (PTMs) regulate protein trafficking, function and degradation, and their in‐depth study plays a significant role in the identification of novel biomarkers and drug targets. Aberrant PTMs of disease‐relevant proteins could trigger pathological pathways, leading to disease progression. Advancements in proteomics enable the generation of patterns or signatures of such modifications, and thus, provide a versatile platform to develop biomarkers based on PTMs. In addition, understanding and targeting the aberrant PTMs of various proteins provide viable avenues for addressing AD drug‐discovery challenges. This review highlights numerous PTMs of proteins relevant to AD and provides an overview of their adverse effects on the protein structure, function and aggregation propensity that contribute to the disease pathology. A critical discussion offers suggestions of methods to develop PTM signatures and interfere with aberrant PTMs to develop viable diagnostic and therapeutic interventions in AD.

The advancements in the field of imaging and diagnostics have been benefitted by the concurrent expansion of molecular probes space to monitor the diverse biological targets and events. The misfolding and aggregation of amyloid β peptide as well as Tau protein generate toxic polymorphic species (referred to as alloforms in this article) which are formally designated as core AD biomarkers by National Institute on Aging and Alzheimer’s Association Research Framework (NIA-AA 2018). Positron emission tomography and magnetic resonance imaging, which are currently the efficient and sophisticated techniques in the clinical diagnosis, are incapable of detection and differentiation of various alloforms besides being not easily operable and affordable by the common people. As a consequence, fluorescence optical imaging has gained great impetus besides many recent technological advancements that have positioned its sensitivity at par with PET and MRI in addition to offering the possibility of alloform detection, rapid analyses and economic benefits to cater to a larger population. In addition, there exists an array of biomarkers or pathophysiological conditions that are known to aggravate the disease progression. This emphasises the importance of molecular tools and methods for the detection of various known as well as yet to be identified AD biomarkers. The molecular and hybrid tools intended for detection and imaging of biomarkers inside the AD brain must cross the blood brain barrier which is one of the persistent challenges for synthetic organic chemists and in this context various strategies are discussed. In this review, we have proposed multiplexed and multimodal analytical approach for the in vitro and in vivo detection and imaging of the core and indirect biomarkers in brain and bio-fluids such as cerebrospinal fluid (CSF) and blood among others to generate characteristic fingerprints to distinguish between healthy and AD patients with precision. Overall, this review offers critical discussions on design, properties, functions, advantages and limitations of the existing molecular probes besides providing current and future prospects for the development of novel diagnostic and theranostic tools for AD.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and a major contributor to dementia cases worldwide. AD is clinically characterized by learning, memory, and cognitive deficits. Accumulation of extracellular amyloid...

We report amino acid, l-dopa and dopamine functionalised naphthalenediimides (NDIs) and the detailed in silico and in vitro studies to identify potential multifunctional modulators of amyloid β toxicity.

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 the primary therapeutic target to ameliorate neuronal toxicity and cognitive deficits. Herein, the design, synthesis, and evaluation of small molecule inhibitors with naphthalene monoimide scaffold to ameliorate in vitro and in vivo amyloid induced neurotoxicity are reported. The detailed studies establish TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. The in silico studies show the 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 shows a significant reduction in cortical and hippocampal amyloid burden in the progressive stages of APP/PS1 AD mice brain. Various behavioral tests demonstrate rescued cognitive deficits. The excellent biocompatibility, blood–brain barrier permeability, and therapeutic efficacy to reduce the amyloid burden make TGR63 a promising candidate for the treatment of AD.

Alzheimer's disease is characterized by the accumulation of amyloid beta (Aβ) and Tau aggregates in the brain, which induces various pathological events resulting in neurodegeneration. There have been continuous efforts to develop modulators of the Aβ and Tau aggregation process to halt or modify disease progression. A few small-molecule-based inhibitors that target both Aβ and Tau pathology have been reported. Here, we report the screening of a targeted library of small molecules to modulate Aβ and Tau aggregation together with their in vitro, in silico and cellular studies. In vitro ThT fluorescence assay, dot blot assay, gel electrophoresis and transmission electron microscopy (TEM) results have shown that thiophenebased lead molecules effectively modulate Aβ aggregation and inhibit Tau aggregation. In silico studies performed by employing molecular docking, molecular dynamics and binding-free energy calculations have helped in understanding the mechanism of interaction of the lead thiophene compounds with Aβ and Tau fibril targets. In cellulo studies revealed that the lead candidate is biocompatible and effectively ameliorates neuronal cells from Aβ and Tau-mediated amyloid toxicity.

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