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Alzheimer's disease (AD) is the most prevalent neurodegenerative disease caused by the deposition of amyloid β (Aβ) fibrils forming extracellular plaques and the development of neurofibrillary tangles (NFT) of intracellular hyperphosphorylated tau protein. Currently, the AD treatments focus on improving cognitive and behavioral symptoms and have limited success. It is imperative to develop novel treatment approaches that can control/inhibit AD progression, especially in the elderly population. Immunotherapy provides a promising and safe treatment option for AD by boosting the patient's immune system. The minimum immune surveillance in the immune-privileged brain, however, makes immunotherapy for AD a challenging endeavor. Therefore, the success of AD immunotherapy depends mainly on the strategy by which therapeutics is delivered to the brain rather than its efficacy. The blood-brain barrier (BBB) is a major obstacle to therapeutic delivery into the brain microenvironment. Various nano-formulations have been exploited to improve the efficacy of AD immunotherapy. In this review, the applications of different types of nano-formulations in augmenting AD immunotherapy have been discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interests in the publication of this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Alzheimer's disease (AD), the most predominant cause of dementia, has evolved tremendously with an escalating frequency, mainly affecting the elderly population. An effective means of delaying, preventing, or treating AD is yet to be achieved. The failure rate of dementia drug trials has been relatively higher than in other disease-related clinical trials. Hence, multi-targeted therapeutic approaches are gaining attention in pharmacological developments., Aims: As an extension of our earlier reports, we have performed docking and molecular dynamic (MD) simulation studies for the same 13 potential ligands against beta-site APP cleaving enzyme 1 (BACE-1) and γ-secretase as a therapeutic target for AD. The In-silico screening of these ligands as potential inhibitors of BACE-1 and γ- secretase was performed using AutoDock enabled PyRx v-0.8. The protein-ligand interactions were analyzed in Discovery Studio 2020 (BIOVIA). The stability of the most promising ligand against BACE-1 and γ- secretase was evaluated by MD simulation using Desmond-2018 (Schrodinger, LLC, NY, USA)., Results: The computational screening revealed that the docking energy values for each of the ligands against both the target enzymes were in the range of -7.0 to -10.1 kcal/mol. Among the 13 ligands, 8 (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed binding energies of ≤-8 kcal/mol against BACE-1 and γ-secretase. For the selected enzyme targets, BACE-1 and γ-secretase, 6Z5 displayed the lowest binding energy of -10.1 and -9.8 kcal/mol, respectively. The MD simulation study confirmed the stability of BACE-6Z5 and γ-secretase-6Z5 complexes and highlighted the formation of a stable complex between 6Z5 and target enzymes., Conclusion: The virtual screening, molecular docking, and molecular dynamics simulation studies revealed the potential of these multi-enzyme targeted ligands. Among the studied ligands, 6Z5 seems to have the best binding potential and forms a stable complex with BACE-1 and γ-secretase. We recommend the synthesis of 6Z5 for future in-vitro and in-vivo studies.

Alzheimer's disease (AD) is a growing global health concern that affects 10% of the population aged above 65 years. A growing body of evidence indicates that multi-targeted drugs might be useful therapeutic options owing to the heterogeneity of AD pathology. The current study exploited advanced computational biology tools to identify ligands that might display effective binding to two protein targets in the context of AD. The present study used in silico virtual screening of small molecules library to identify effectiveness against two AD targets viz. acetyl cholinesterase (AChE) and glycogen synthase kinase-3β (GSK-3β). PyRX-Python prescription with AutodockVina was used to generate binding energy profiles. Further screening was accomplished using SwissADME and molecular interaction studies. The present study obtained 48 ligands (absolute binding energy >8 kcal/mol), by virtual screening of 100 ligands. Among those, 13 ligands (BRW, 6VK, 6Z5, SMH, X37, 55E, 65 A, IQ6, 6VL, 6VM, F1B, 6Z2 and GVP) were selected based on blood brain barrier (BBB) permeability, acceptable ADME properties as well as their molecular interaction profiles with the aforementioned AD-targets. The present study has predicted certain molecules that appear worthy to be tested for effectiveness against two AD targets, namely AChE and GSK-3β. However, the results warrant further wet laboratory validation, as computational studies are merely predictive in nature. This approach might be useful for future treatment of AD.Communicated by Ramaswamy H. Sarma.

Background: With the burgeoning worldwide aging population, the incidence of Alzheimer's disease (AD) and its associated disorders is continuously rising. To appraise other relevant drug targets that could lead to potent enzyme targeting, 13 previously predicted ligands (shown favorable binding with AChE (acetylcholinesterase) and GSK-3 (glycogen synthase kinase) were screened for targeting 3 different enzymes, namely butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B) to possibly meet the unmet medical need of better AD treatment., Materials and Methods: The study utilized in silico screening of 13 ligands against BChE, MAO-A and MAOB using PyRx-Python prescription 0.8. The visualization of the active interaction of studied compounds with targeted proteins was performed by Discovery Studio 2020 (BIOVIA)., Results: The computational screening of studied ligands revealed the docking energies in the range of -2.4 to -11.3 kcal/mol for all the studied enzymes. Among the 13 ligands, 8 ligands (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed the binding energies of ≤ -8.0 kcal/mol towards BChE, MAO-A and MAO-B. The ligand 6Z5 was found to be the most potent inhibitor of BChE and MAO-B, with a binding energy of -9.7 and -10.4 kcal mol, respectively. Molecular dynamics simulation of BChE-6Z5 and MAO-B-6Z5 complex confirmed the formation of a stable complex., Conclusion: Our computational screening, molecular docking, and molecular dynamics simulation studies revealed that the above-mentioned enzymes targeted ligands might expedite the future design of potent anti-AD drugs generated on this chemical scaffold., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder. Recent reports suggest that it affects more than 36 million people worldwide and accounts 60-80% of all cases of dementia. It is characterised by aberrations of multiple interactive systems and pathways, which ultimately lead to memory loss and cognitive dysfunction. The exact mechanisms and initial triggering factors that underpin the known pathological defects in AD remain to be fully elucidated. In addition, an effective treatment strategy to reduce the progression of AD is yet to be achieved. In the light of above-mentioned facts, our article deals with the exploration of the mitochondrial defect and oxidative stress leading to this devastating disease. In this communication, we have highlighted specific mitochondrial and antioxidant-directed approach to ameliorate and manage AD. Nonetheless, new approaches should also be investigated that could tackle various molecular events involved in AD pathogenicity.

Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β-amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances. Approximately, 60%-80% of all cases of dementia in the world are patients with AD. In view of the continuous rise of this disease especially in the aged population, there is a dire need to come up with a novel compound and/or mixture that could work against this devastating disease. In this regard, the best is to rely on natural compounds rather than synthetic ones, because natural compounds are easily available, cost-effective, and comparatively less toxic. To serve this purpose, lately, scientific community has started exploring the possibility of using different polyphenols either solitary or in combination that can serve as therapeutics against AD. In the current article, we have summarized the role of various polyphenols, namely quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, and caffeic acid as an inhibitor of cholinesterase for the treatment of AD. We have also tried to uncover the mechanistic insight on the action of these polyphenols against AD pathogenicity., (© 2018 John Wiley & Sons Ltd.)

Alzheimer's disease (AD) is a well-known cause of memory loss and dementia in elderly people all across the world. It is pathophysiologically characterized by the extracellular deposition of amyloid beta (Aβ) proteins and retention of intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins. Several enzymes, such as lipoxygenases, acetylcholinesterases, secretases, glycogen synthase kinase 3, caspases, sirtuins have been reported to actively participate in the pathogenesis of AD. Due to the limited drug for the management of AD till now (only memantine and four other acetylcholinesterase inhibitors), there is an urgent need to find out the novel inhibitors that could specifically act against these enzymes or therapeutically important targets, and barricade or decelerate AD progression. In this current review, we aim to unravel various enzymes and their potential inhibitors that could be exploited against AD pathogenesis. We have also covered several other important miscellaneous targets which could be used as AD therapeutics., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Alzheimer's disease (AD) is an irreversible multifaceted neurodegenerative disorder that gradually degrades neuronal cells. It is the most frequent cause of memory loss and dementia in elderly individuals worldwide. The extracellular deposition of beta amyloid (Aβ), intracellular neurofibrillary tangles (NFTs) retention, neuronal decline and neurotransmitter system derangement are the patho-physiological marker of this devastated disease Objective: In view of limited treatment option and their success rate, there is an urgent need to explore the vast array of proteomes for the management of AD. These proteins could be therapeutically targeted to prevent the progression of this disease. In the present review, we tried to uncover several proteins that could be exploited in AD therapeutics., Conclusion: Based on our article, we conclude that proteome based AD treatment needs more refinements and approaches to achieve the desired success rate., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Alzheimer's disease (AD) is an irreversible multifaceted neurodegenerative disorder that gradually degrades neuronal cells. Presently, it is the most common reason for the memory loss and dementia in older individuals. It is patho-physiologically described by extracellular amyloid beta (Aβ) deposition, intracellular neurofibrillary tangles (NFTs) retention, neuronal decline, and neurotransmitter system derangement. Various receptors such as nicotinic acetylcholine, N-methyl-D-aspartate, insulin, serotonin, adenosine, and histamine are actively involved in the physiological progression of AD. Till date memantine and only four other acetylcholinesterase inhibitors have been approved for the treatment of AD by US Food and Drug Administration (US-FDA). Hence, there is a critical need to explore and develop novel and helpful management systems which could specifically target different receptors involved in AD progression. We believe that these receptors targeting will either impede the disease onset or slow down its pathogenesis. In the present review, we tried to uncover some receptors that could be blocked by novel inhibitors and ultimately used for the therapeutic management of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The two most common forms of dementia are Alzheimer's disease (AD) followed by vascular dementia (VaD), together accounting for a whopping 60-80% of total dementia cases worldwide. Even though these diseases are recognized as 'common', they still remain underdiagnosed. Recent research suggests that AD and VaD are closely intertwined. The symptoms of AD and VaD can be similar and the two conditions can occur simultaneously. A large number of patients diagnosed with AD have also been reported with VaD-caused brain damage. Moreover, both the diseases have been reported to have similar risk factors. The overlap between these diseases is important because the lifestyle changes and medications prescribed to curb one of these diseases may also help curb the other. In the present review, we present an inclusive outline of parallelism between AD and VaD by exploring the potential commonalities at the mechanistic and therapeutic levels.

Despite extensive research for over two decades, the medical science is yet to assign the exact aetiology and mode of progression of Alzheimer's disease (AD). The modern era of AD drug development began with the proposal of the cholinergic hypothesis of memory impairment. Since then, despite the proposal and phase trials of many therapeutic options, only few drugs have shown some efficacy and safety. The reasons behind this have been many including the ineffectiveness of tested drugs and inadequacy of clinical development methods. In this manuscript, we present an account of modern structural, functional and molecular imaging developed for AD therapy. A comprehensive review of all the current and future treatment options for AD, ranging from cholinergic drugs, NMDA receptor antagonist, immunotherapy, drugs reducing Aβ production, and drugs targeting tau protein and mitochondrial dysfunction has also been provided. However, the failure of all the proposed treatment options to provide a complete cure of AD has been pushing for the need of new therapies. The recent advent of nano-drugs has been proposed to provide crucial breakthroughs in AD therapy. Hence, a detailed outline of the usage and applications of nano-drugs in AD therapy, and outstanding developments in nanodrug metabolism and disposition has been discussed.

Neurodegeneration is the progressive loss of neuronal structure and function, which ultimately leads to neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and Huntington's disease. Even after the recent significant advances in neurobiology, the above-mentioned disorders continue to haunt the global population. Several studies have suggested the role of specific environmental and genetic risk factors associated with these disorders. However, the exact mechanism associated with the progression of these disorders still needs to be elucidated. In the recent years, sophisticated research has revealed interesting association of prominent neurodegenerative disorders such as AD and PD with chronic diseases such as cancer, diabetes, and cardiovascular diseases. Several common molecular mechanisms such as generation of free radicals, oxidative DNA damage, aberrations in mitochondrial DNA, and dysregulation of apoptosis have been highlighted as possible points of connection. The present review summarizes the possible mechanism of coexistence of AD and PD with other chronic diseases., (© 2014 John Wiley & Sons Ltd.)

Chronic infection can cause slow progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. Due to the fact that specific bacterial ligands can increase the expression of proinflammatory molecules that can activate innate and adaptive immune systems, inflammation may play a significant role in the pathogenesis of Alzheimer's disease (AD). Furthermore, there is a significant association between AD and various types of spirochete. Periodontitis is a prevalent and persistent peripheral infection that is associated with gram-negative anaerobic bacteria and is capable of showing localized and systemic infections in the host. Periodontal disease related pathogens and their inflammatory products contribute to systemic inflammation and the pathogenesis of AD. In this minireview, we propose a hypothetical link between periodontitis, type 2 diabetes and AD. We also present the possible mechanistic links between periodontitis-related inflammation, type 2 diabetes and AD. Since this condition is treatable, periodontitis may be a readily-modifiable risk factor for AD.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two devastating diseases that are currently incurable. Epidemiological, clinical and pathological evidence has confirmed the co-existence of these two disorders. Moreover, there has been promising progress made in the identification of the pathological linkage between T2DM and AD in the last decade. Hence, developing common treatment strategies for these diseases is important. Currently, enzyme targeting is a potential strategy to cure many diseases. In this communication, we tried to summarize the single enzymetargeted therapeutic approach for the treatment of AD and T2DM. This field of research continues to be active and progressive in identifying many promising enzymes that are involved in both diseases. Based on this review article, we also believe that enzyme inhibition is a promising and reliable strategy for the treatment of many incurable diseases. In the future, we expect that the scientific community will be able to develop common enzyme inhibitors for the treatment of both AD and T2DM.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two progressive and devastating health disorders afflicting millions of people worldwide. The probability and incidence of both have increased considerably in recent years consequent to increased longevity and population growth. Progressively more links are being continuously found between inflammation and central nervous system disorders like AD, Parkinson's disease, Huntington's disease, motor neuron disease, multiple sclerosis, stroke, traumatic brain injury and even cancers of the nervous tissue. The depth of the relationship depends on the timing and extent of anti- or pro-inflammatory gene expression. Inflammation has also been implicated in T2DM. Misfolding and fibrillization (of tissue specific and/or non-specific proteins) are features common to both AD and T2DM and are induced by as well as contribute to inflammation and stress (oxidative/ glycation). This review appraises the roles of inflammation and abnormalities in the insulin signaling system as important shared features of T2DM and AD. The capacity of anti-cholinesterases in reducing the level of certain common inflammatory markers in particular if they may provide therapeutic potential to mitigate awry mechanisms leading to AD.

In general, proteins can only execute their various biological functions when they are appropriately folded. Their amino acid sequence encodes the relevant information required for correct three-dimensional folding, with or without the assistance of chaperones. The challenge associated with understanding protein folding is currently one of the most important aspects of the biological sciences. Misfolded protein intermediates form large polymers of unwanted aggregates and are involved in the pathogenesis of many human diseases, including Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM). AD is one of the most prevalent neurological disorders and has worldwide impact; whereas T2DM is considered a metabolic disease that detrementally influences numerous organs, afflicts some 8% of the adult population, and shares many risk factors with AD. Research data indicates that there is a widespread conformational change in the proteins involved in AD and T2DM that form β-sheet like motifs. Although conformation of these β-sheets is common to many functional proteins, the transition from α-helix to β-sheet is a typical characteristic of amyloid deposits. Any abnormality in this transition results in protein aggregation and generation of insoluble fibrils. The abnormal and toxic proteins can interact with other native proteins and consequently catalyze their transition into the toxic state. Both AD and T2DM are prevalent in the aged population. AD is characterized by the accumulation of amyloid-β (Aβ) in brain, while T2DM is characterized by the deposition of islet amyloid polypeptide (IAPP, also known as amylin) within beta-cells of the pancreas. T2DM increases pathological angiogenesis and immature vascularisation. This also leads to chronic cerebral hypoperfusion, which results in dysfunction and degeneration of neuroglial cells. With an abundance of common mechanisms underpinning both disorders, a significant question that can be posed is whether T2DM leads to AD in aged individuals and the associations between other protein misfolding diseases., Competing Interests: The authors confirm that this article content has no conflict of interest.

Nitric oxide- (NO-) dependent oxidative stress results in mitochondrial ultrastructural alterations and DNA damage in cases of Alzheimer disease (AD). However, little is known about these pathways in human cancers, especially during the development as well as the progression of primary brain tumors and metastatic colorectal cancer. One of the key features of tumors is the deficiency in tissue energy that accompanies mitochondrial lesions and formation of the hypoxic smaller sized mitochondria with ultrastructural abnormalities. We speculate that mitochondrial involvement may play a significant role in the etiopathogenesis of cancer. Recent studies also demonstrate a potential link between AD and cancer, and anticancer drugs are being explored for the inhibition of AD-like pathology in transgenic mice. Severity of the cancer growth, metastasis, and brain pathology in AD (in animal models that mimic human AD) correlate with the degree of mitochondrial ultrastructural abnormalities. Recent advances in the cell-cycle reentry of the terminally differentiated neuronal cells indicate that NO-dependent mitochondrial abnormal activities and mitotic cell division are not the only important pathogenic factors in pathogenesis of cancer and AD, but open a new window for the development of novel treatment strategies for these devastating diseases.

There is a strong cerebrovascular component to brain aging, Alzheimer disease, and vascular dementia. Foods, common drugs, and the polyphenolic compounds contained in wine modulate health both directly and through the gut microbiota. This observation and novel findings centered on nutrition, biochemistry, and metabolism, as well as the newer insights we gain into the microbiota-gut-brain axis, now lead us to propose a shunt to this classic triad, which involves the heart and cerebrovascular systems. The French paradox and prosaic foods, as they relate to the microbiota-gut-brain axis and neurodegenerative diseases, are discussed in this manuscript, which is the second part of a two-part series of concept papers addressing the notion that the microbiota and host liver metabolism all play roles in brain and heart health. [ABSTRACT FROM AUTHOR]