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Therapeutics and Pathophysiology of Cognitive Dysfunction
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Therapeutics and Pathophysiology of Cognitive Dysfunction

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 November 2025 | Viewed by 1738

Special Issue Editor

Dr. Maheedhar Kodali

E-Mail Website
Guest Editor
Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, 1114 TAMU, College Station, TX 77842, USA
Interests: neurodegenerative diseases; therapeutic strategies; cognitive function; cellular and transcriptomic alterations

Special Issue Information

Dear Colleagues,

Cognitive dysfunction typified by impaired attention, learning, memory, and problem-solving skills is generally referred to as ‘brain fog’ associated with neuroimmune imbalance in multiple neurodegenerative diseases, malignancies, and associated metabolic conditions. In neuropsychiatric diseases, cognitive impairments are associated with suicidal tendencies, which are predictive of depression relapse and are frequently retained in individuals in remission from depressive episodes. Nonetheless, cognitive dysfunction has a significant effect on quality of life but is clinically underreported, likely due to its limitation in detection at subclinical levels. Therefore, strategies aimed at enhancing the detection threshold of cognitive impairments and attenuating these deficits through modulating the underlying pathologies, such as diminishing neuroinflammation, enhancing neurogenesis, and metabolic fitness have garnered significant attention. The possibility of non-pharmacological methods like music therapy and pharmaceutical methods, particularly those that target the GABAergic system, to alleviate cognitive symptoms has recently been investigated. To increase the quality of life, however, this domain requires more attention.

Dr. Maheedhar Kodali
Guest Editor

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.

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Keywords

  • cognition
  • neurologic diseases
  • neuroinflammation

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Published Papers (3 papers)

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Research

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19 pages, 1688 KiB  
Article
Shorter Telomere Length in Individuals with Neurocognitive Disorder and APOE ε4 Genotype
by Paola Mejía-Ortiz, Alma Delia Genis-Mendoza, Ramon Ramírez Villanueva, Susana López Ramírez, Rafael Guzmán Sánchez, Thalia Fernández, Jorge Sigg-Alonso and Humberto Nicolini-Sánchez
Int. J. Mol. Sci. 2025, 26(10), 4577; https://doi.org/10.3390/ijms26104577 - 10 May 2025
Viewed by 444
Abstract
Neurocognitive disorders (NCD) are neurodegenerative diseases characterized by decline or loss of cognitive functions. Aging and the APOE genotype have been identified as major risk factors. Telomere length (TL) has been proposed as a biomarker of aging, with shorter TL associated with cognitive [...] Read more.
Neurocognitive disorders (NCD) are neurodegenerative diseases characterized by decline or loss of cognitive functions. Aging and the APOE genotype have been identified as major risk factors. Telomere length (TL) has been proposed as a biomarker of aging, with shorter TL associated with cognitive decline. This study investigated the relationship between TL and the APOE genotype in individuals with cognitive impairments (CIs). A total of 170 participants aged >55 years were included. Cognitive function was assessed using the MMSE and MoCA tests. Relative telomere quantification and APOE genotype were determined by real-time PCR. A significant association was observed between shorter TL and an increased risk of CI (p < 0.001). Although APOE ε4 is a known genetic risk factor, its association with CI was less clear in this study population, as a considerable proportion of ε4 carriers did not present cognitive impairment (p < 0.05). However, ε4 carriers with CI tended to have shorter TL than those with non-cognitive impairment (NCI-SMC). Furthermore, fewer years of education were strongly correlated with higher CI risk (p < 0.0001). Overall, individuals with both shorter telomeres and lower educational levels exhibited the highest risk of CI. APOE ε4 may contribute to telomere shortening. Full article
(This article belongs to the Special Issue Therapeutics and Pathophysiology of Cognitive Dysfunction)
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Review

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40 pages, 1669 KiB  
Review
Microglia-Mediated Neuroinflammation Through Phosphatidylinositol 3-Kinase Signaling Causes Cognitive Dysfunction
by Mohammad Nazmul Hasan Maziz, Srikumar Chakravarthi, Thidar Aung, Phone Myint Htoo, Wana Hla Shwe, Sergey Gupalo, Manglesh Waran Udayah, Hardev Singh, Mohammed Shahjahan Kabir, Rajesh Thangarajan and Maheedhar Kodali
Int. J. Mol. Sci. 2025, 26(15), 7212; https://doi.org/10.3390/ijms26157212 - 25 Jul 2025
Viewed by 34
Abstract
Microglia, as the immune guardians of the central nervous system (CNS), have the ability to maintain neural homeostasis, respond to environmental changes, and remodel the synaptic landscape. However, persistent microglial activation can lead to chronic neuroinflammation, which can alter neuronal signaling pathways, resulting [...] Read more.
Microglia, as the immune guardians of the central nervous system (CNS), have the ability to maintain neural homeostasis, respond to environmental changes, and remodel the synaptic landscape. However, persistent microglial activation can lead to chronic neuroinflammation, which can alter neuronal signaling pathways, resulting in accelerated cognitive decline. Phosphoinositol 3-kinase (PI3K) has emerged as a critical driver, connecting inflammation to neurodegeneration, serving as the nexus of numerous intracellular processes that govern microglial activation. This review focuses on the relationship between PI3K signaling and microglial activation, which might lead to cognitive impairment, inflammation, or even neurodegeneration. The review delves into the components of the PI3K signaling cascade, isoforms, and receptors of PI3K, as well as the downstream effects of PI3K signaling, including its effectors such as protein kinase B (Akt) and mammalian target of rapamycin (mTOR) and the negative regulator phosphatase and tensin homolog (PTEN). Experiments have shown that the overproduction of certain cytokines, coupled with abnormal oxidative stress, is a consequence of poor PI3K regulation, resulting in excessive synapse pruning and, consequently, impacting learning and memory functions. The review also highlights the implications of autonomously activated microglia exhibiting M1/M2 polarization driven by PI3K on hippocampal, cortical, and subcortical circuits. Conclusions from behavioral studies, electrophysiology, and neuroimaging linking cognitive performance and PI3K activity were evaluated, along with new approaches to therapy using selective inhibitors or gene editing. The review concludes by highlighting important knowledge gaps, including the specific effects of different isoforms, the risks associated with long-term pathway modulation, and the limitations of translational potential, underscoring the crucial role of PI3K in mitigating cognitive impairment driven by neuroinflammation. Full article
(This article belongs to the Special Issue Therapeutics and Pathophysiology of Cognitive Dysfunction)
43 pages, 1978 KiB  
Review
Positive AMPA and Kainate Receptor Modulators and Their Therapeutic Potential in CNS Diseases: A Comprehensive Review
by Alina Vialko, Paulina Chałupnik and Ewa Szymańska
Int. J. Mol. Sci. 2025, 26(13), 6450; https://doi.org/10.3390/ijms26136450 - 4 Jul 2025
Viewed by 716
Abstract
Ionotropic glutamate receptors—including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors—play a pivotal role in excitatory signaling in the central nervous system (CNS), which is particularly important for learning and memory processes. Among them, AMPA and kainate receptors (known as [...] Read more.
Ionotropic glutamate receptors—including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors—play a pivotal role in excitatory signaling in the central nervous system (CNS), which is particularly important for learning and memory processes. Among them, AMPA and kainate receptors (known as ‘non-NMDA’ receptors) have gained increasing attention as therapeutic targets for various CNS disorders. Positive allosteric modulators (PAMs) of these receptors enhance their activity without directly activating them, offering a promising strategy to fine-tune glutamatergic signaling with potentially fewer side effects compared to orthosteric agonists. This review presents a comprehensive overview of recent advances in the development of AMPA and kainate receptor PAMs. We classify the most relevant modulators into main chemotype groups and discuss their binding modes, structure–activity relationships, and efficacy as determined through in vitro and in vivo studies. Additionally, we provide an overview of AMPA receptor PAMs that have entered into clinical trials over the past few decades. The increasing interest in kainate receptor PAMs is also mentioned, underlining their emerging role in future neuropharmacological strategies. Full article
(This article belongs to the Special Issue Therapeutics and Pathophysiology of Cognitive Dysfunction)
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