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Pharmaceuticals
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New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases
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New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 22 October 2024 | Viewed by 16135

Special Issue Editors

Prof. Dr. Robert Joseph Shmookler Reis

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Guest Editor
1. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
2. Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
Interests: Alzheimer’s disease; aging; determinants of longevity; neurodegenerative diseases
Dr. Meenakshisundaram Balasubramaniam

E-Mail Website
Guest Editor
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Interests: drug screening in silico; protein-protein interactions; bioinformatics
Dr. Srinivas Ayyadevara

E-Mail Website
Guest Editor
1. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
2. Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
Interests: Alzheimer’s disease; aging; determinants of longevity; neurodegenerative diseases; cardiovascular disease; cachexia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) features two diagnostic types of aggregate: extracellular Aβ amyloids, and intra-neuronal tau tangles.  However, many other proteins have also been identified within AD aggregates and often feature AD-specific phosphorylations or other post-translational modifications [PTMs] 1,2.  The upregulation of several kinases has been implicated as possibly driving AD pathology, but other PTMs (e.g., acetylation, oxidation, glycosylation) can also induce protein misfolding and aggregation.  In this Special Issue of Pharmaceuticals, we welcome papers that describe research addressing any part of the progression from the identification of novel drug targets, the in silico screening of structural libraries, the validation of candidate molecules in cell or animal model systems, and ultimately culminating in human trials.  The highest priority will be given to work presenting novel targets and evidence for their potential utility in preventing or ameliorating Alzheimer’s disease or other neurological diseases, and any other diseases where protein aggregation due to altered proteostasis is noted, and to the identification and validation of early biomarkers associated with cognitive impairment and its progression to AD.

1   Ganne, A., Balasubramaniam, M., Griffin, W. S. T., Shmookler Reis, R. J. & Ayyadevara, S. Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer's Disease. Pharmaceutics 14, doi:10.3390/pharmaceutics14071354 (2022).

2   Ayyadevara, S. et al. Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls. Aging Cell 15, 924-939, doi:10.1111/acel.12501 (2016).

Prof. Dr. Robert Joseph Shmookler Reis
Dr. Meenakshisundaram Balasubramaniam
Dr. Srinivas Ayyadevara
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • Parkinson’s disease
  • Huntington’s disease
  • amyotrophic lateral sclerosis
  • neurodegeneration
  • inflammation
  • anti-inflammatory drugs
  • post-translational modifications
  • protein misfolding
  • protein aggregation

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Published Papers (7 papers)

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Research

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13 pages, 1306 KiB  
Article
Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer’s Disease Risk: A Retrospective Cohort Proof-of-Concept Study
by Tiffany W. Chow, Mark Raupp, Matthew W. Reynolds, Siying Li, Gwendolyn E. Kaeser and Jerold Chun
Pharmaceuticals 2024, 17(4), 408; https://doi.org/10.3390/ph17040408 - 22 Mar 2024
Viewed by 7027
Abstract
Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer’s disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people [...] Read more.
Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer’s disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted. Full article
(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)
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20 pages, 7352 KiB  
Article
Identification of Indazole-Based Thiadiazole-Bearing Thiazolidinone Hybrid Derivatives: Theoretical and Computational Approaches to Develop Promising Anti-Alzheimer’s Candidates
by Yousaf Khan, Shoaib Khan, Rafaqat Hussain, Wajid Rehman, Aneela Maalik, Urooba Gulshan, Mohamed W. Attwa, Hany W. Darwish, Hazem A. Ghabbour and Nawab Ali
Pharmaceuticals 2023, 16(12), 1667; https://doi.org/10.3390/ph16121667 - 30 Nov 2023
Cited by 3 | Viewed by 1169
Abstract
A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1–17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied [...] Read more.
A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1–17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 μM to 26.73 ± 0.84 μM (AChE) and 0.89 ± 0.12 μM to 27.08 ± 0.19 μM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 μM for AChE) and (1.35 ± 0.37 μM for BuChE), respectively. Specifically, the derivatives 1–17, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 μM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 μM (against BuChE), respectively.The structure–activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data. Full article
(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)
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19 pages, 4350 KiB  
Article
Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan
by Samuel Kakraba, Srinivas Ayyadevara, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Suresh Bowroju, Narsimha Reddy Penthala, Ramani Atluri, Steven W. Barger, Sue T. Griffin, Peter A. Crooks and Robert J. Shmookler Reis
Pharmaceuticals 2023, 16(10), 1498; https://doi.org/10.3390/ph16101498 - 20 Oct 2023
Cited by 2 | Viewed by 2454
Abstract
Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, [...] Read more.
Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ1–42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and “healthspan” (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15–30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality. Full article
(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)
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Review

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24 pages, 2644 KiB  
Review
Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer’s Disease
by Pontus Forsell, Cristina Parrado Fernández, Boel Nilsson, Johan Sandin, Gunnar Nordvall and Märta Segerdahl
Pharmaceuticals 2024, 17(8), 997; https://doi.org/10.3390/ph17080997 - 28 Jul 2024
Viewed by 744
Abstract
Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer’s disease has been described. [...] Read more.
Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer’s disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer’s disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function. Full article
(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)
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19 pages, 1054 KiB  
Review
Non-Apoptotic Programmed Cell Death as Targets for Diabetic Retinal Neurodegeneration
by Yingjia Lin, Shuping Ke, Weiqing Ye, Biyao Xie and Zijing Huang
Pharmaceuticals 2024, 17(7), 837; https://doi.org/10.3390/ph17070837 - 26 Jun 2024
Viewed by 1232
Abstract
Diabetic retinopathy (DR) remains the leading cause of blindness among the global working-age population. Emerging evidence underscores the significance of diabetic retinal neurodegeneration (DRN) as a pivotal biomarker in the progression of vasculopathy. Inflammation, oxidative stress, neural cell death, and the reduction in [...] Read more.
Diabetic retinopathy (DR) remains the leading cause of blindness among the global working-age population. Emerging evidence underscores the significance of diabetic retinal neurodegeneration (DRN) as a pivotal biomarker in the progression of vasculopathy. Inflammation, oxidative stress, neural cell death, and the reduction in neurotrophic factors are the key determinants in the pathophysiology of DRN. Non-apoptotic programmed cell death (PCD) plays a crucial role in regulating stress response, inflammation, and disease management. Therapeutic modalities targeting PCD have shown promising potential for mitigating DRN. In this review, we highlight recent advances in identifying the role of various PCD types in DRN, with specific emphasis on necroptosis, pyroptosis, ferroptosis, parthanatos, and the more recently characterized PANoptosis. In addition, the therapeutic agents aimed at the regulation of PCD for addressing DRN are discussed. Full article
(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)
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33 pages, 7616 KiB  
Review
Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease
by Yiting Zhao, Man Lin, Fengguang Zhai, Jun Chen and Xiaofeng Jin
Pharmaceuticals 2024, 17(6), 782; https://doi.org/10.3390/ph17060782 - 14 Jun 2024
Viewed by 975
Abstract
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental factors, and age-related neurodegenerative processes. Numerous studies have demonstrated that aberrant functioning of the ubiquitin–proteasome system (UPS) plays a crucial role in the [...] Read more.
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental factors, and age-related neurodegenerative processes. Numerous studies have demonstrated that aberrant functioning of the ubiquitin–proteasome system (UPS) plays a crucial role in the initiation and progression of PD. Notably, E3 ubiquitin ligases serve as pivotal components determining substrate specificity within UPS and are intimately associated with the regulation of various proteins implicated in PD pathology. This review comprehensively summarizes the mechanisms by which E3 ubiquitin ligases and deubiquitinating enzymes modulate PD-associated proteins and signaling pathways, while exploring the intricate relationship between UPS dysfunctions and PD etiology. Furthermore, this article discusses recent research advancements regarding inhibitors targeting PD-related E3 ubiquitin ligases. Full article
(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)
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18 pages, 1187 KiB  
Review
Innovative Therapeutic Strategies in Alzheimer’s Disease: A Synergistic Approach to Neurodegenerative Disorders
by Sarfaraz K. Niazi, Matthias Magoola and Zamara Mariam
Pharmaceuticals 2024, 17(6), 741; https://doi.org/10.3390/ph17060741 - 6 Jun 2024
Viewed by 1008
Abstract
Alzheimer’s disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a [...] Read more.
Alzheimer’s disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system’s role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-β (Aβ) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, opening new possibilities for treatment. Despite these advancements, conventional therapies for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, underscoring the need for innovative solutions. This necessity has led to the incorporation advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions. Full article
(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)
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