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Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 7152

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Dr. Mark M. Stecker

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Fresno Institute of Neuroscience, University of California, San Francisco, CA 94720, USA
Interests: neurology; neurophysiology; neuroscience; big data; physics
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The neurodegenerative diseases include many disorders such as Alzheimer’s disease, Parkinson’s disease, multiple system atrophy, fronto-temporal dementia, and amyotrophic lateral sclerosis. They represent a serious international public health problem affecting over 50 million people with only very limited disease modifying treatments. Our understanding of the events that trigger the degenerative process and facilitate its relentless progression are limited because of the gradual onset of subtle cognitive and motor changes and the difficulty diagnosing these diseases in their early stages. Although tau, amyloid, alpha-synuclein, TDP-43 or other pathologies are present in the later stages of the disease, it is not clear that they represent the original pathophysiologic causes.

This special issue will focus on novel hypotheses regarding the cause, progression, or treatment of neurodegenerative diseases. This could be in the form of reinterpreting existing data or new data from molecular or neurophysiologic studies with a translational component. Research using big data sets that biochemical, molecular, or physiologic data are of extreme interest but any approach will be considered.

This special issue can be a means to bring together scholars from different backgrounds to contribute to this important topic.

Dr. Mark M. Stecker
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

neurodegenerative diseases
dementia
bioinformatics
neuroscience

Published Papers (6 papers)

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Research

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22 pages, 7039 KiB

Open AccessArticle

Computational Modeling of Extrasynaptic NMDA Receptors: Insights into Dendritic Signal Amplification Mechanisms

by Mark Makarov, Michele Papa and Eduard Korkotian

Int. J. Mol. Sci. 2024, 25(8), 4235; https://doi.org/10.3390/ijms25084235 - 11 Apr 2024

Viewed by 363

Abstract

Dendritic structures play a pivotal role in the computational processes occurring within neurons. Signal propagation along dendrites relies on both passive conduction and active processes related to voltage-dependent ion channels. Among these channels, extrasynaptic N-methyl-D-aspartate channels (exNMDA) emerge as a significant contributor. Prior studies have mainly concentrated on interactions between synapses and nearby exNMDA (100 nm–10 µm from synapse), activated by presynaptic membrane glutamate. This study concentrates on the correlation between synaptic inputs and distal exNMDA (>100 µm), organized in clusters that function as signal amplifiers. Employing a computational model of a dendrite, we elucidate the mechanism underlying signal amplification in exNMDA clusters. Our findings underscore the pivotal role of the optimal spatial positioning of the NMDA cluster in determining signal amplification efficiency. Additionally, we demonstrate that exNMDA subunits characterized by a large conduction decay constant. Specifically, NR2B subunits exhibit enhanced effectiveness in signal amplification compared to subunits with steeper conduction decay. This investigation extends our understanding of dendritic computational processes by emphasizing the significance of distant exNMDA clusters as potent signal amplifiers. The implications of our computational model shed light on the spatial considerations and subunit characteristics that govern the efficiency of signal amplification in dendritic structures, offering valuable insights for future studies in neurobiology and computational neuroscience. Full article

(This article belongs to the Special Issue Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies)

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17 pages, 7755 KiB

Open AccessArticle

Amyloid-β Effects on Peripheral Nerve: A New Model System

by Mark M. Stecker, Ankita Srivastava and Allison B. Reiss

Int. J. Mol. Sci. 2023, 24(19), 14488; https://doi.org/10.3390/ijms241914488 - 23 Sep 2023

Viewed by 1017

Abstract

Although there are many biochemical methods to measure amyloid-β (Aβ)42 concentration, one of the critical issues in the study of the effects of Aβ42 on the nervous system is a simple physiological measurement. The in vitro rat sciatic nerve model is employed and the nerve action potential (NAP) is quantified with different stimuli while exposed to different concentrations of Aβ42. Aβ42 predominantly reduces the NAP amplitude with minimal effects on other parameters except at low stimulus currents and short inter-stimulus intervals. The effects of Aβ42 are significantly concentration-dependent, with a maximum reduction in NAP amplitude at a concentration of 70 nM and smaller effects on the NAP amplitude at higher and lower concentrations. However, even physiologic concentrations in the range of 70 pM did reduce the NAP amplitude. The effects of Aβ42 became maximal 5–8 h after exposure and did not reverse during a 30 min washout period. The in vitro rat sciatic nerve model is sensitive to the effects of physiologic concentrations of Aβ42. These experiments suggest that the effect of Aβ42 is a very complex function of concentration that may be the result of amyloid-related changes in membrane properties or sodium channels. Full article

(This article belongs to the Special Issue Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies)

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13 pages, 6499 KiB

Open AccessArticle

Adipocyte-Derived Small Extracellular Vesicles from Patients with Alzheimer Disease Carry miRNAs Predicted to Target the CREB Signaling Pathway in Neurons

by Rachael A. Batabyal, Ankush Bansal, Laura Reck Cechinel, Kayla Authelet, Madeleine Goldberg, Evan Nadler, C. Dirk Keene, Suman Jayadev, Kimiko Domoto-Reilly, Gail Li, Elaine Peskind, Kazue Hashimoto-Torii, Dedra Buchwald and Robert J. Freishtat

Int. J. Mol. Sci. 2023, 24(18), 14024; https://doi.org/10.3390/ijms241814024 - 13 Sep 2023

Cited by 1 | Viewed by 1671

Abstract

Alzheimer disease (AD) is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, synaptic dysfunction, and progressive dementia. Midlife obesity increases the risk of developing AD. Adipocyte-derived small extracellular vesicles (ad-sEVs) have been implicated as a mechanism in several obesity-related diseases. We hypothesized that ad-sEVs from patients with AD would contain miRNAs predicted to downregulate pathways involved in synaptic plasticity and memory formation. We isolated ad-sEVs from the serum and cerebrospinal fluid (CSF) of patients with AD and controls and compared miRNA expression profiles. We performed weighted gene co-expression network analysis (WGCNA) on differentially expressed miRNAs to identify highly interconnected clusters correlating with clinical traits. The WGCNA identified a module of differentially expressed miRNAs, in both the serum and CSF, that was inversely correlated with the Mini-Mental State Examination scores. Within this module, miRNAs that downregulate CREB signaling in neurons were highly represented. These results demonstrate that miRNAs carried by ad-sEVs in patients with AD may downregulate CREB signaling and provide a potential mechanistic link between midlife obesity and increased risk of AD. Full article

(This article belongs to the Special Issue Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies)

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37 pages, 13840 KiB

Open AccessArticle

The Proteome Profile of Olfactory Ecto-Mesenchymal Stem Cells-Derived from Patients with Familial Alzheimer’s Disease Reveals New Insights for AD Study

by Lory J. Rochín-Hernández, Miguel A. Jiménez-Acosta, Lorena Ramírez-Reyes, María del Pilar Figueroa-Corona, Víctor J. Sánchez-González, Maribel Orozco-Barajas and Marco A. Meraz-Ríos

Int. J. Mol. Sci. 2023, 24(16), 12606; https://doi.org/10.3390/ijms241612606 - 09 Aug 2023

Cited by 4 | Viewed by 1853

Abstract

Alzheimer’s disease (AD), the most common neurodegenerative disease and the first cause of dementia worldwide, has no effective treatment, and its pathological mechanisms are not yet fully understood. We conducted this study to explore the proteomic differences associated with Familial Alzheimer’s Disease (FAD) in olfactory ecto-mesenchymal stem cells (MSCs) derived from PSEN1 (A431E) mutation carriers compared with healthy donors paired by age and gender through two label-free liquid chromatography-mass spectrometry approaches. The first analysis compared carrier 1 (patient with symptoms, P1) and its control (healthy donor, C1), and the second compared carrier 2 (patient with pre-symptoms, P2) with its respective control cells (C2) to evaluate whether the protein alterations presented in the symptomatic carrier were also present in the pre-symptom stages. Finally, we analyzed the differentially expressed proteins (DEPs) for biological and functional enrichment. These proteins showed impaired expression in a stage-dependent manner and are involved in energy metabolism, vesicle transport, actin cytoskeleton, cell proliferation, and proteostasis pathways, in line with previous AD reports. Our study is the first to conduct a proteomic analysis of MSCs from the Jalisco FAD patients in two stages of the disease (symptomatic and presymptomatic), showing these cells as a new and excellent in vitro model for future AD studies. Full article

(This article belongs to the Special Issue Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies)

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Review

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20 pages, 1367 KiB

Open AccessReview

Respiratory Dysfunction in Alzheimer’s Disease—Consequence or Underlying Cause? Applying Animal Models to the Study of Respiratory Malfunctions

by Agnieszka Wrzesień, Kryspin Andrzejewski, Monika Jampolska and Katarzyna Kaczyńska

Int. J. Mol. Sci. 2024, 25(4), 2327; https://doi.org/10.3390/ijms25042327 - 16 Feb 2024

Viewed by 1079

Abstract

Alzheimer’s disease (AD) is a neurodegenerative brain disease that is the most common cause of dementia among the elderly. In addition to dementia, which is the loss of cognitive function, including thinking, remembering, and reasoning, and behavioral abilities, AD patients also experience respiratory disturbances. The most common respiratory problems observed in AD patients are pneumonia, shortness of breath, respiratory muscle weakness, and obstructive sleep apnea (OSA). The latter is considered an outcome of Alzheimer’s disease and is suggested to be a causative factor. While this narrative review addresses the bidirectional relationship between obstructive sleep apnea and Alzheimer’s disease and reports on existing studies describing the most common respiratory disorders found in patients with Alzheimer’s disease, its main purpose is to review all currently available studies using animal models of Alzheimer’s disease to study respiratory impairments. These studies on animal models of AD are few in number but are crucial for establishing mechanisms, causation, implementing potential therapies for respiratory disorders, and ultimately applying these findings to clinical practice. This review summarizes what is already known in the context of research on respiratory disorders in animal models, while pointing out directions for future research. Full article

(This article belongs to the Special Issue Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies)

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Other

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7 pages, 878 KiB

Open AccessPerspective

The “Hit and Run” Hypothesis for Alzheimer’s Disease Pathogenesis

by Tal Ganz and Tamir Ben-Hur

Int. J. Mol. Sci. 2024, 25(6), 3245; https://doi.org/10.3390/ijms25063245 - 13 Mar 2024

Viewed by 631

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide. Emerging research has challenged the conventional notion of a direct correlation between amyloid deposition and neurodegeneration in AD. Recent studies have suggested that amyloid and Tau deposition act as a central nervous system (CNS) innate immune driver event, inducing chronic microglial activation that increases the susceptibility of the AD brain to the neurotoxicity of infectious insults. Although modifiable risk factors account for up to 50% of AD risk, the mechanisms by which they interact with the core process of misfolded protein deposition and neuroinflammation in AD are unclear and require further investigation. This update introduces a novel perspective, suggesting that modifiable risk factors act as external insults that, akin to infectious agents, cause neurodegeneration by inducing recurrent acute neurotoxic microglial activation. This pathological damage occurs in AD pathology-primed regions, creating a “hit and run” mechanism that leaves no discernible pathological trace of the external insult. This model, highlighting microglia as a pivotal player in risk factor-mediated neurodegeneration, offers a new point of view on the complex associations of modifiable risk factors and proteinopathy in AD pathogenesis, which may act in parallel to the thoroughly studied amyloid-driven Tau pathology, and strengthens the therapeutic rationale of combining immune modulation with tight control of risk factor-driven insults. Full article

(This article belongs to the Special Issue Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies)

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Novel Hypotheses for Dementia and Neurodegenerative Diseases: From Molecular Mechanisms to Therapies

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