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Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics

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: 30 September 2024 | Viewed by 7508

Special Issue Editor

Dr. Lilach Soreq

E-Mail Website
Guest Editor
Molecular Neuroscience Department, University College London, London, UK
Interests: ageing; Alzheimer’s disease; bioinformatics; RNA-Seq; Parkinson’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging is an inevitable process common to humans, and a major risk factor for several age-related diseases, including neurodegenerative diseases. During human aging, neurodegenerative diseases and their associated cognitive deficits, which affect human health and life, are prevalent. Alzheimer's disease (AD) is one of the most common neurodegenerative brain diseases, and a main mark of it is the functional decline and disruption of the blood–brain barrier, which is characterized by the accumulation of amyloid-β plaques, neural disassembly, synaptic dysfunction, and cellular damage to neurons as well as other brain cells in the brain parenchyma. These can lead to memory impairment, behavioral changes, loss of cognitive function, and dementia.

The present Special Issue in the International Journal of Molecular Sciences aims to gain insight into the pathogenesis of Alzheimer's disease, barrier dysfunction, neuronal transmission, brain changes associated with aging, oxidative stress, mitochondrial dysfunction, and the identification of amyloid, tau, and p-tau, as well as other biomarkers.

Dr. Lilach Soreq
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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Published Papers (7 papers)

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Research

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15 pages, 2950 KiB  
Article
Reduced Expression of CLEC4G in Neurons Is Associated with Alzheimer’s Disease
by Xinwei Feng, Fangfang Qi, Yuying Huang, Ge Zhang and Wenbin Deng
Int. J. Mol. Sci. 2024, 25(9), 4621; https://doi.org/10.3390/ijms25094621 - 24 Apr 2024
Viewed by 287
Abstract
CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer’s disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G [...] Read more.
CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer’s disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management. Full article
(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)
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17 pages, 3584 KiB  
Article
A Stable Micellar Formulation of RAD001 for Intracerebroventricular Delivery and the Treatment of Alzheimer’s Disease and Other Neurological Disorders
by Laura Gianessi, Alessandro Magini, Roberto Dominici, Stefano Giovagnoli and Diego Dolcetta
Int. J. Mol. Sci. 2023, 24(24), 17478; https://doi.org/10.3390/ijms242417478 - 14 Dec 2023
Viewed by 757
Abstract
A large body of evidence, replicated in many mouse models of Alzheimer’s disease (AD), supports the therapeutic efficacy of the oral mammalian target of rapamycin inhibitors (mTOR-Is). Our preliminary data show that intracerebroventricular (ICV) administration of everolimus (RAD001) soon after clinical onset greatly [...] Read more.
A large body of evidence, replicated in many mouse models of Alzheimer’s disease (AD), supports the therapeutic efficacy of the oral mammalian target of rapamycin inhibitors (mTOR-Is). Our preliminary data show that intracerebroventricular (ICV) administration of everolimus (RAD001) soon after clinical onset greatly diminished cognitive impairment and the intracellular beta amyloid and neurofibrillary tangle load. However, RAD001 shows >90% degradation after 7 days in solution at body temperature, thus hampering the development of proper therapeutic regimens for patients. To overcome such a drawback, we developed a stable, liquid formulation of mTOR-Is by loading RAD001 into distearoylphosphatidylethanolamine–polyethylene glycol 2000 (DSPE-PEG2000) micelles using the thin layer evaporation method. The formulation showed efficient encapsulation of RAD001 and a homogeneous colloidal size and stabilised RAD001, with over 95% of activity preserved after 14 days at 37 °C with a total decay only occurring after 98 days. RAD001-loaded DSPE-PEG2000 micelles were unchanged when stored at 4 and 25 °C over the time period investigated. The obtained formulation may represent a suitable platform for expedited clinical translation and effective therapeutic regimens in AD and other neurological diseases. Full article
(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)
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18 pages, 29578 KiB  
Article
Second Wave, Late-Stage Neuroinflammation in Cleared Brains of Aged 5xFAD Alzheimer’s Mice Detected by Macrolaser Light Sheet Microscopy Imaging
by Suk Hyun Lee and Hye Joo Son
Int. J. Mol. Sci. 2023, 24(23), 17058; https://doi.org/10.3390/ijms242317058 - 02 Dec 2023
Viewed by 859
Abstract
This study leverages the innovative imaging capabilities of macrolaser light-sheet microscopy to elucidate the 3D spatial visualization of AD-associated neuropathologic networks in the transparent brains of 44-week-old 5xFAD mice. Brain samples from ten AD and seven control mice were prepared through a hydrophilic [...] Read more.
This study leverages the innovative imaging capabilities of macrolaser light-sheet microscopy to elucidate the 3D spatial visualization of AD-associated neuropathologic networks in the transparent brains of 44-week-old 5xFAD mice. Brain samples from ten AD and seven control mice were prepared through a hydrophilic tissue-clearing pipeline and immunostained with thioflavin S (β-amyloid), anti-CD11b antibody (microglia), and anti-ACSA-2 antibody (astrocytes). The 5xFAD group exhibited significantly higher average total surface volumes of β-amyloid accumulation than the control group (AD, 898,634,368 µm3 [383,355,488–1,324,986,752]; control, 33,320,178 µm3 [11,156,785–65,390,988], p = 0.0006). Within the AD group, there was significant interindividual and interindividual variability concerning the number and surface volume of individual amyloid particles throughout the entire brain. In the context of neuroinflammation, the 5xFAD group showed significantly higher average total surface volumes of anti-ACSA-2-labeled astrocytes (AD, 59,064,360 µm3 [27,815,500–222,619,280]; control, 20,272,722 µm3 [9,317,288–27,223,352], p = 0.0047) and anti-CD11b labeled microglia (AD, 51,210,100 µm3 [15,309,118–135,532,144]; control, 23,461,593 µm3 [14,499,170–27,924,110], p = 0.0162) than the control group. Contrary to the long-standing finding that early-stage neuroinflammation precedes the subsequent later-stage of neurodegeneration, our data reveal that the second wave, late-stage active neuroinflammation persists in the aged AD brains, even as they continue to show signs of ongoing neurodegeneration and significant amyloid accumulation. Full article
(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)
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Review

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14 pages, 1624 KiB  
Review
Astrocyte–Neuron Interaction via the Glutamate–Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration
by Marta Sidoryk-Węgrzynowicz, Kamil Adamiak and Lidia Strużyńska
Int. J. Mol. Sci. 2024, 25(5), 3050; https://doi.org/10.3390/ijms25053050 - 06 Mar 2024
Viewed by 733
Abstract
Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood–brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These [...] Read more.
Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood–brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate–glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders. Full article
(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)
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16 pages, 343 KiB  
Review
Recent Aspects of Periodontitis and Alzheimer’s Disease—A Narrative Review
by Dominika Cichońska, Magda Mazuś and Aida Kusiak
Int. J. Mol. Sci. 2024, 25(5), 2612; https://doi.org/10.3390/ijms25052612 - 23 Feb 2024
Viewed by 1345
Abstract
Periodontitis is an inflammatory condition affecting the supporting structures of the teeth. Periodontal conditions may increase the susceptibility of individuals to various systemic illnesses, including Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative condition characterized by a gradual onset and progressive deterioration, making it [...] Read more.
Periodontitis is an inflammatory condition affecting the supporting structures of the teeth. Periodontal conditions may increase the susceptibility of individuals to various systemic illnesses, including Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative condition characterized by a gradual onset and progressive deterioration, making it the primary cause of dementia, although the exact cause of the disease remains elusive. Both Alzheimer’s disease and periodontitis share risk factors and clinical studies comparing the associations and occurrence of periodontitis among individuals with Alzheimer’s disease have suggested a potential correlation between these conditions. Brains of individuals with Alzheimer’s disease have substantiated the existence of microorganisms related to periodontitis, especially Porphyromonas gingivalis, which produces neurotoxic gingipains and may present the capability to breach the blood–brain barrier. Treponema denticola may induce tau hyperphosphorylation and lead to neuronal apoptosis. Lipopolysaccharides—components of bacterial cell membranes and mediators of inflammation—also have an impact on brain function. Further research could unveil therapeutic approaches targeting periodontal pathogens to potentially alleviate AD progression. Full article
(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)
27 pages, 820 KiB  
Review
Multi-Omic Blood Biomarkers as Dynamic Risk Predictors in Late-Onset Alzheimer’s Disease
by Oneil G. Bhalala, Rosie Watson and Nawaf Yassi
Int. J. Mol. Sci. 2024, 25(2), 1231; https://doi.org/10.3390/ijms25021231 - 19 Jan 2024
Viewed by 1292
Abstract
Late-onset Alzheimer’s disease is the leading cause of dementia worldwide, accounting for a growing burden of morbidity and mortality. Diagnosing Alzheimer’s disease before symptoms are established is clinically challenging, but would provide therapeutic windows for disease-modifying interventions. Blood biomarkers, including genetics, proteins and [...] Read more.
Late-onset Alzheimer’s disease is the leading cause of dementia worldwide, accounting for a growing burden of morbidity and mortality. Diagnosing Alzheimer’s disease before symptoms are established is clinically challenging, but would provide therapeutic windows for disease-modifying interventions. Blood biomarkers, including genetics, proteins and metabolites, are emerging as powerful predictors of Alzheimer’s disease at various timepoints within the disease course, including at the preclinical stage. In this review, we discuss recent advances in such blood biomarkers for determining disease risk. We highlight how leveraging polygenic risk scores, based on genome-wide association studies, can help stratify individuals along their risk profile. We summarize studies analyzing protein biomarkers, as well as report on recent proteomic- and metabolomic-based prediction models. Finally, we discuss how a combination of multi-omic blood biomarkers can potentially be used in memory clinics for diagnosis and to assess the dynamic risk an individual has for developing Alzheimer’s disease dementia. Full article
(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)
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13 pages, 2403 KiB  
Review
Advances in Alzheimer’s Disease-Associated Aβ Therapy Based on Peptide
by Cunli Wang, Shuai Shao, Na Li, Zhengyao Zhang, Hangyu Zhang and Bo Liu
Int. J. Mol. Sci. 2023, 24(17), 13110; https://doi.org/10.3390/ijms241713110 - 23 Aug 2023
Cited by 2 | Viewed by 1413
Abstract
Alzheimer’s disease (AD) urgently needs innovative treatments due to the increasing aging population and lack of effective drugs and therapies. The amyloid fibrosis of AD-associated β-amyloid (Aβ) that could induce a series of cascades, such as oxidative stress and inflammation, is a critical [...] Read more.
Alzheimer’s disease (AD) urgently needs innovative treatments due to the increasing aging population and lack of effective drugs and therapies. The amyloid fibrosis of AD-associated β-amyloid (Aβ) that could induce a series of cascades, such as oxidative stress and inflammation, is a critical factor in the progression of AD. Recently, peptide-based therapies for AD are expected to be great potential strategies for the high specificity to the targets, low toxicity, fast blood clearance, rapid cell and tissue permeability, and superior biochemical characteristics. Specifically, various chiral amino acids or peptide-modified interfaces draw much attention as effective manners to inhibit Aβ fibrillation. On the other hand, peptide-based inhibitors could be obtained through affinity screening such as phage display or by rational design based on the core sequence of Aβ fibrosis or by computer aided drug design based on the structure of Aβ. These peptide-based therapies can inhibit Aβ fibrillation and reduce cytotoxicity induced by Aβ aggregation and some have been shown to relieve cognition in AD model mice and reduce Aβ plaques in mice brains. This review summarizes the design method and characteristics of peptide inhibitors and their effect on the amyloid fibrosis of Aβ. We further describe some analysis methods for evaluating the inhibitory effect and point out the challenges in these areas, and possible directions for the design of AD drugs based on peptides, which lay the foundation for the development of new effective drugs in the future. Full article
(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)
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