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Molecular Mechanisms of Dementia 2.0
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Molecular Mechanisms of Dementia 2.0

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 (29 November 2023) | Viewed by 11951

Special Issue Editor

Dr. Mariagiovanna Cantone

E-Mail Website
Guest Editor
Neurology Unit, University Hospital Policlinico “G. Rodolico-San Marco”, Via Santa Sofia 78, 95123 Catania, Italy
Interests: cerebrovascular diseases; stroke; depression; dementia; non-invasive brain stimulation; neuroplasticity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dementias and the other neurodegenerative disorders that affect memory, cognition, and behavior are a public health priority across the developed world. It has been estimated that the number of people with dementia will double every 20 years.

So far, the most pressing challenge has been to discriminate the different forms of dementia or their earliest stages from the features of normal brain aging. In the case of vascular dementia it is possible to carry out a preventive strategy based on a closer and more accurate control of vascular risk factors. In the case of degenerative dementias, although several mechanisms have been hypothesized at both the cellular and neuronal network levels, the exact molecular mechanisms that lead to dementia are not well-understood.

Moreover, the presence of clinical similarities between dementias raises the question as to whether common molecular pathways might explain shared clinical symptoms.

This Special Issue of the International Journal of Molecular Sciences focuses on dementia and welcomes both original research articles and review papers that deal with the emerging molecular mechanisms of dementia.

Dr. Mariagiovanna Cantone
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.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • neurodegenerative disorders
  • dementia
  • molecular pathways

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Published Papers (7 papers)

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Editorial

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3 pages, 162 KiB  
Editorial
Molecular Mechanisms of Dementia 2.0
by Mariagiovanna Cantone
Int. J. Mol. Sci. 2024, 25(13), 7110; https://doi.org/10.3390/ijms25137110 - 28 Jun 2024
Viewed by 611
Abstract
Dementia and the other neurodegenerative disorders represent a complex pathophysiological process [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia 2.0)

Research

Jump to: Editorial

14 pages, 3505 KiB  
Article
Cognitive Impairment in Nonagenarians: Potential Metabolic Mechanisms Revealed by the Synergy of In Silico Gene Expression Modeling and Pathway Enrichment Analysis
by Aleksandra Mamchur, Elena Zelenova, Irina Dzhumaniiazova, Veronika Erema, Daria Kashtanova, Mikhail Ivanov, Maria Bruttan, Mariia Gusakova, Mikhail Terekhov, Vladimir Yudin, Antonina Rumyantseva, Lorena Matkava, Irina Strazhesko, Ruslan Isaev, Anna Kruglikova, Lilit Maytesyan, Irina Tarasova, Olga Beloshevskaya, Elen Mkhitaryan, Sergey Kraevoy, Olga Tkacheva and Sergey Yudinadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(6), 3344; https://doi.org/10.3390/ijms25063344 - 15 Mar 2024
Cited by 1 | Viewed by 1456
Abstract
Previous studies examining the molecular and genetic basis of cognitive impairment, particularly in cohorts of long-living adults, have mainly focused on associations at the genome or transcriptome level. Dozens of significant dementia-associated genes have been identified, including APOE, APOC1, and TOMM40. However, most [...] Read more.
Previous studies examining the molecular and genetic basis of cognitive impairment, particularly in cohorts of long-living adults, have mainly focused on associations at the genome or transcriptome level. Dozens of significant dementia-associated genes have been identified, including APOE, APOC1, and TOMM40. However, most of these studies did not consider the intergenic interactions and functional gene modules involved in cognitive function, nor did they assess the metabolic changes in individual brain regions. By combining functional analysis with a transcriptome-wide association study, we aimed to address this gap and examine metabolic pathways in different areas of the brain of older adults. The findings from our previous genome-wide association study in 1155 older adults, 179 of whom had cognitive impairment, were used as input for the PrediXcan gene prediction algorithm. Based on the predicted changes in gene expression levels, we conducted a transcriptome-wide association study and functional analysis using the KEGG and HALLMARK databases. For a subsample of long-living adults, we used logistic regression to examine the associations between blood biochemical markers and cognitive impairment. The functional analysis revealed a significant association between cognitive impairment and the expression of NADH oxidoreductase in the cerebral cortex. Significant associations were also detected between cognitive impairment and signaling pathways involved in peroxisome function, apoptosis, and the degradation of lysine and glycan in other brain regions. Our approach combined the strengths of a transcriptome-wide association study with the advantages of functional analysis. It demonstrated that apoptosis and oxidative stress play important roles in cognitive impairment. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia 2.0)
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31 pages, 47653 KiB  
Article
Mesenchymal Stem Cells from Familial Alzheimer’s Patients Express MicroRNA Differently
by Lory J. Rochín-Hernández, Lory S. Rochín-Hernández, Mayte L. Padilla-Cristerna, Andrea Duarte-García, Miguel A. Jiménez-Acosta, María P. Figueroa-Corona and Marco A. Meraz-Ríos
Int. J. Mol. Sci. 2024, 25(3), 1580; https://doi.org/10.3390/ijms25031580 - 27 Jan 2024
Cited by 4 | Viewed by 2006
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the predominant form of dementia globally. No reliable diagnostic, predictive techniques, or curative interventions are available. MicroRNAs (miRNAs) are vital to controlling gene expression, making them valuable biomarkers for diagnosis and prognosis. This study [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the predominant form of dementia globally. No reliable diagnostic, predictive techniques, or curative interventions are available. MicroRNAs (miRNAs) are vital to controlling gene expression, making them valuable biomarkers for diagnosis and prognosis. This study examines the transcriptome of olfactory ecto-mesenchymal stem cells (MSCs) derived from individuals with the PSEN1(A431E) mutation (Jalisco mutation). The aim is to determine whether this mutation affects the transcriptome and expression profile of miRNAs and their target genes at different stages of asymptomatic, presymptomatic, and symptomatic conditions. Expression microarrays compare the MSCs from mutation carriers with those from healthy donors. The results indicate a distinct variation in the expression of miRNAs and mRNAs among different symptomatologic groups and between individuals with the mutation. Using bioinformatics tools allows us to identify target genes for miRNAs, which in turn affect various biological processes and pathways. These include the cell cycle, senescence, transcription, and pathways involved in regulating the pluripotency of stem cells. These processes are closely linked to inter- and intracellular communication, vital for cellular functioning. These findings can enhance our comprehension and monitoring of the disease’s physiological processes, identify new disorder indicators, and develop innovative treatments and diagnostic tools for preventing or treating AD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia 2.0)
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13 pages, 991 KiB  
Article
Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia
by Maria Rosário Almeida, Miguel Tábuas-Pereira, Inês Baldeiras, Marisa Lima, João Durães, João Massano, Madalena Pinto, Catarina Cruto and Isabel Santana
Int. J. Mol. Sci. 2024, 25(1), 511; https://doi.org/10.3390/ijms25010511 - 29 Dec 2023
Cited by 2 | Viewed by 1123
Abstract
In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the [...] Read more.
In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia 2.0)
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11 pages, 1567 KiB  
Article
Sex-Related Disparities in the Resting State Functional Connectivity of the Locus Coeruelus and Salience Network in Preclinical Alzheimer’s Disease
by Yoo Hyun Um, Sheng-Min Wang, Dong Woo Kang, Sunghwan Kim, Chang Uk Lee, Donghyeon Kim, Yeong Sim Choe, Regina E. Y. Kim, Soyoung Lee and Hyun Kook Lim
Int. J. Mol. Sci. 2023, 24(20), 15092; https://doi.org/10.3390/ijms242015092 - 11 Oct 2023
Cited by 1 | Viewed by 1247
Abstract
Recent studies have demonstrated the pivotal role of locus coeruleus (LC) and salience network (SN) resting state functional connectivity (rsFC) changes in the early stage of Alzheimer’s disease (AD). Moreover, sex has been a crucial point of discussion in understanding AD pathology. We [...] Read more.
Recent studies have demonstrated the pivotal role of locus coeruleus (LC) and salience network (SN) resting state functional connectivity (rsFC) changes in the early stage of Alzheimer’s disease (AD). Moreover, sex has been a crucial point of discussion in understanding AD pathology. We aimed to demonstrate the sex-related disparities in the functional connectivity (FC) of the SN and LC in preclinical AD. A total of 89 cognitively normal patients with evidence of amyloid beta (Aβ) accumulation ([18F] flutemetamol +) were recruited in the study. A seed-to-voxel analysis was conducted to measure the LC and SN rsFC differences between sexes. In addition, sex by Aβ interactive effects on FC values were analyzed with a general linear model. There were statistically significant sex by regional standardized uptake value ratio (SUVR) interactions in the LC FC with the parietal, frontal, and occipital cortices. Moreover, there was a significant sex by global SUVR interaction in the SN FC with the temporal cortex. The findings suggest that there are differential patterns of LC FC and SN FC in males and females with preclinical AD, which interact with regional Aβ deposition. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia 2.0)
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14 pages, 2087 KiB  
Article
Cognitive Normal Older Adults with APOE-2 Allele Show a Distinctive Functional Connectivity Pattern in Response to Cerebral Aβ Deposition
by Sheng-Min Wang, Dong Woo Kang, Yoo Hyun Um, Sunghwan Kim, Regina E. Y. Kim, Donghyeon Kim, Chang Uk Lee and Hyun Kook Lim
Int. J. Mol. Sci. 2023, 24(14), 11250; https://doi.org/10.3390/ijms241411250 - 8 Jul 2023
Cited by 2 | Viewed by 1528
Abstract
The ε2 allele of apolipoprotein E (ε2) has neuroprotective effects against beta-amyloid (Aβ) pathology in Alzheimer’s disease (AD). However, its impact on the functional connectivity and hub efficiency in cognitively normal older adults (CN) with ε2 is unclear. We investigated the functional connectivity [...] Read more.
The ε2 allele of apolipoprotein E (ε2) has neuroprotective effects against beta-amyloid (Aβ) pathology in Alzheimer’s disease (AD). However, its impact on the functional connectivity and hub efficiency in cognitively normal older adults (CN) with ε2 is unclear. We investigated the functional connectivity differences in the default mode network (DMN), salience network, and central executive network (CEN) between A-PET-negative (N = 29) and A-PET-positive (N = 15) CNs with ε2/ε2 or ε2/ε3 genotypes. The A-PET-positive CNs exhibited a lower anterior DMN functional connectivity, higher posterior DMN functional connectivity, and increased CEN functional connectivity compared to the A-PET-negative CNs. Cerebral Aβ retention was negatively correlated with anterior DMN functional connectivity and positively correlated with posterior DMN and anterior CEN functional connectivity. A graph theory analysis showed that the A-PET-positive CNs displayed a higher betweenness centrality in the middle frontal gyrus (left) and medial fronto-parietal regions (left). The betweenness centrality in the middle frontal gyrus (left) was positively correlated with Aβ retention. Our findings reveal a reversed anterior–posterior dissociation in the DMN functional connectivity and heightened CEN functional connectivity in A-PET-positive CNs with ε2. Hub efficiencies, measured by betweenness centrality, were increased in the DMN and CEN of the A-PET-positive CNs with ε2. These results suggest unique functional connectivity responses to Aβ pathology in CN individuals with ε2. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia 2.0)
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27 pages, 8549 KiB  
Article
Genetic Networks of Alzheimer’s Disease, Aging, and Longevity in Humans
by Timothy Balmorez, Amy Sakazaki and Shin Murakami
Int. J. Mol. Sci. 2023, 24(6), 5178; https://doi.org/10.3390/ijms24065178 - 8 Mar 2023
Cited by 7 | Viewed by 3491
Abstract
Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer’s disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of [...] Read more.
Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer’s disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value < 1.00 × 10−5 using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p < 1.00 × 10−5, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression (p = 4.05 × 10−11) including ApoE, SOD2, TP53, and TGFB1 (p = 2.84 × 10−10); protein metabolism and SUMOylation, including E3 ligases and target proteins (p = 1.08 × 10−7); ERBB4 signal transduction (p = 2.69 × 10−6); the immune system, including IL-3 and IL-13 (p = 3.83 × 10−6); programmed cell death (p = 4.36 × 10−6); and platelet degranulation (p = 8.16 × 10−6), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 (p = 7.64 × 10−8), plasma lipoprotein assembly, remodeling and clearance (p < 4.02 × 10−6), and the metabolism of fat-soluble vitamins (p = 1.96 × 10−5). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Dementia 2.0)
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