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Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 27162

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Dr. A. N. M. Mamun-Or-Rashid

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Guest Editor

Anti-Aging Medical Research Center and Glycation Stress Research Center, Graduate School of Life and Medical Sciences, Doshisha University, Kyoto 602-8566, Japan
Interests: cell death; cell differentiation; bone remodeling; Alzheimer; aging; glycative stress; oxidative stress; redox biology

Special Issue Information

Dear Colleagues,

This Special Issue will concentrate on the aging process in in vitro, animal, or human models, the resulting changes in cellular and molecular levels, structural and functional changes of proteins, lipids, genes, enzymes, and their relationship with the development of Alzheimer’s disease (AD). As glycative stress, oxidative stress, and ER stress are reported to be elevated with age, this elevation may accelerate the progression of AD. Amyloid-beta production, deposition, and plaque formation may not be the only reasons behind the progression of AD, as there could be other proteins responsible that are unknown so far. Most often, we focus on the upregulated genes, but the downregulated genes may be the cause we usually neglect. Environmental factors, pollutants, food habits, lifestyle, alcohol consumption, and smoking could accelerate or slow down AD pathogenesis. We are still searching for the best lifestyle to avoid or slow down AD. There is a possibility, for example, that drugs currently being used for the treatment of other diseases may lead to better controlling AD, but there have been no research studies to confirm this as of yet. Human, animal, or microbial enzymes may have the potential to clear the amyloid plaque. Bioinformatics tools may help to identify new targets or design and develop new effective drug candidates for clinical trials.

This Special Issue welcomes original research or review articles focused on the cellular and molecular events upon aging that promote the onset and advancement of AD.

Dr. A. N. M. Mamun-Or-Rashid
Guest Editor

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Keywords

Alzheimer’s disease
aging, glycative and oxidative stress
risk factors
Neuroinflammation
neurodegeneration
lifestyle
food habits
pollution
therapeutic approaches

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Published Papers (9 papers)

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18 pages, 3167 KiB

Open AccessArticle

Piperazine Derivative Stabilizes Actin Filaments in Primary Fibroblasts and Binds G-Actin In Silico

by Nikita Zernov, Viktor Ghamaryan, Ani Makichyan, Daria Melenteva, Lernik Hunanyan and Elena Popugaeva

Curr. Issues Mol. Biol. 2022, 44(11), 5191-5208; https://doi.org/10.3390/cimb44110353 - 25 Oct 2022

Cited by 1 | Viewed by 1962

Abstract

Alzheimer’s disease (AD) is characterized by synaptic dysfunction, which is expressed through the loss of dendritic spines and changes in their morphology. Pharmacological compounds that are able to protect spines in the AD brain are suggested to be novel drugs that would be able to slow down the disease progression. We have recently shown that a positive modulator of transient receptor potential cation channel subfamily C member 6 (TRPC6), the compound N-(2-chlorophenyl)-2-(4-phenylpiperazine-1-yl) acetamide (51164), causes the upregulation of postsynaptic neuronal store-operated calcium entry, maintains mushroom spine percentage, and recovers synaptic plasticity in amyloidogenic mouse models of Alzheimer’s disease. Here, using confocal microscopy and calcium imaging methods, we present the experimental data indicating that 51164 possesses an alternative mechanism of action. We demonstrated that 51164 can increase the mushroom spine percentage in neurons with the downregulated activity of TRPC6-dependent neuronal store-operated calcium entry. Moreover, we report the binding of 51164 to G-actin in silico. We observed that 51164 interacts with Lys 336, Asp157, and Ser14 of G-actin, amino acids involved in the stabilization/polymerization of the G-actin structure. We showed that interactions of 51164 with G-actin are much stronger in comparison to the well-characterized F-actin stabilizing and polymerizing drug, jasplakinolide. The obtained results suggest an alternative protective mechanism of 51164 that is related to the preservation of actin filaments in vitro. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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9 pages, 286 KiB

Open AccessArticle

Analysis of SOD2 rs4880 Genetic Variant in Patients with Alzheimer’s Disease

by Vasileios Siokas, Polyxeni Stamati, Georgia Pateraki, Ioannis Liampas, Athina-Maria Aloizou, Daniil Tsirelis, Anastasia Nousia, Markos Sgantzos, Grigorios Nasios, Dimitrios P. Bogdanos and Efthimios Dardiotis

Curr. Issues Mol. Biol. 2022, 44(10), 4406-4414; https://doi.org/10.3390/cimb44100302 - 21 Sep 2022

Cited by 5 | Viewed by 2504

Abstract

A few gene loci that contribute to Alzheimer’s Disease (AD) onset have been identified. Few studies have been published about the relationship between SOD2 rs4880 single nucleotide variant and AD, revealing inconsistent results. Therefore, the aim of the current study is to further examine the role of the SOD2 rs4880 in AD. We performed a case-control study with a total of 641 subjects (320 patients with probable AD, and 321 healthy controls). The statistical analysis was performed assuming five genetic models. The threshold for statistical significance was set at 0.05. The results revealed no association between SOD2 rs4880 and AD in any of the assumed genetic models that were examined [log-additive OR = 0.95 (0.76–1.19), over-dominant OR = 1.15 (0.85–1.57), recessive OR = 0.85 (0.59–1.22), dominant OR = 1.03 (0.72–1.47), and co-dominant OR1 = 1.10 (0.75–1.60) and OR2 = 0.90 (0.58–1.40)]. Adjustment for sex and subgroup analyses based on sex did not reveal any statistically significant results either. Based on our findings, SOD2 rs4880 does not appear to play a determining role in the risk of developing AD. Larger studies are warranted to elucidate the connection between rs4880 and AD. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

13 pages, 4723 KiB

Open AccessArticle

Effects of Acute Sepsis on Cellular Dynamics and Amyloid Formation in a Mouse Model of Alzheimer’s Disease

by Alexandra Daniela Rotaru-Zavaleanu, Alexandru Ionuț Neacșu, Adela-Daria Neacșu, Daniel Pirici, Eugen Osiac, Bogdan Cătălin and Dan Ionuț Gheonea

Curr. Issues Mol. Biol. 2022, 44(9), 3822-3834; https://doi.org/10.3390/cimb44090262 - 24 Aug 2022

Cited by 1 | Viewed by 1925

Abstract

Our objective was to investigate how sepsis influences cellular dynamics and amyloid formation before and after plaque formation. As such, APP-mice were subjected to a polymicrobial abdominal infection resulting in sepsis at 2 (EarlySepsis) and 4 (LateSepsis) months of age. Behavior was tested before sepsis and at 5 months of age. We could not detect any short-term memory or exploration behavior alterations in APP-mice that were subjected to Early or LateSepsis. Immunohistochemical analysis revealed a lower area of NeuN⁺ and Iba1⁺ signal in the cortex of Late compared with EarlySepsis animals (p = 0.016 and p = 0.01), with an increased astrogliosis in LateSepsis animals compared with WT-Sepsis (p = 0.0028), EarlySepsis (p = 0.0032) and the APP-Sham animals (p = 0.048). LateSepsis animals had larger areas of amyloid compared with both EarlySepsis (p = 0.0018) and APP-Sham animals (p = 0.0024). Regardless of the analyzed markers, we were not able to detect any cellular difference at the hippocampal level between groups. We were able to detect an increased inflammatory response around hippocampal plaques in LateSepsis compared with APP-Sham animals (p = 0.0003) and a decrease of AQP4 signal far from Sma⁺ vessels. We were able to show experimentally that an acute sepsis event before the onset of plaque formation has a minimal effect; however, it could have a major impact after its onset. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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19 pages, 3733 KiB

Open AccessArticle

1-L Transcription in Alzheimer’s Disease

by Jozef Nahalka

Curr. Issues Mol. Biol. 2022, 44(8), 3533-3551; https://doi.org/10.3390/cimb44080243 - 9 Aug 2022

Cited by 5 | Viewed by 3271

Abstract

Alzheimer’s disease is a very complex disease and better explanations and models are needed to understand how neurons are affected and microglia are activated. A new model of Alzheimer’s disease is presented here, the β-amyloid peptide is considered an important RNA recognition/binding peptide. 1-L transcription revealed compatible sequences with AAUAAA (PAS signal) and UUUC (class III ARE rich in U) in the Aβ peptide, supporting the peptide–RNA regulatory model. When a hypothetical model of fibril selection with the prionic character of amyloid assemblies is added to the peptide-RNA regulatory model, the downregulation of the PI3K-Akt pathway and the upregulation of the PLC-IP3 pathway are well explained. The model explains why neurons are less protected from inflammation and why microglia are activated; why mitochondria are destabilized; why the autophagic flux is destabilized; and why the post-transcriptional attenuation of the axonal signal “noise” is interrupted. For example, the model suggests that Aβ peptide may post-transcriptionally control ELAVL2 (ELAV-like RNA binding protein 2) and DCP2 (decapping mRNA protein 2), which are known to regulate RNA processing, transport, and stability. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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9 pages, 2870 KiB

Open AccessArticle

Evaluation of Ectopic Mitochondrial DNA in HeLa Cells

by Mohammad T. Hussan, Noriko Matsui and Hideaki Matsui

Curr. Issues Mol. Biol. 2022, 44(3), 1215-1223; https://doi.org/10.3390/cimb44030080 - 2 Mar 2022

Viewed by 3645

Abstract

The presence of ectopic DNA in the cytoplasm induces inflammation and cell death. It has been widely reported that leakage of nuclear DNA into the cytoplasm can mainly be sensed by cyclic GMP-AMP synthase (cGAS). We recently reported that mitochondria-derived cytoplasmic double-stranded DNA (dsDNA) that has escaped lysosomal degradation induces significant cytotoxicity in cultured cells and in vivo. Cytoplasmic mitochondrial DNA is assumed to be involved in various diseases and disorders, and more and more papers have been published confirming this. On the other hand, the current method for evaluating mitochondrial DNA in the cytoplasm may not be quantitative. Here, we introduce in detail a method to evaluate ectopic mitochondrial DNA in cells. This method is useful in basic research as well as in the study of aging, Parkinson’s disease, Alzheimer’s disease, heart failure, autoimmune diseases, cancer, and other conditions. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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Review

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17 pages, 726 KiB

Open AccessReview

The Quest for Neurodegenerative Disease Treatment—Focusing on Alzheimer’s Disease Personalised Diets

by Matei Palimariciuc, Ioana-Miruna Balmus, Bogdan Gireadă, Alin Ciobica, Roxana Chiriță, Alin-Constantin Iordache, Mihai Apostu and Romeo Petru Dobrin

Curr. Issues Mol. Biol. 2023, 45(2), 1519-1535; https://doi.org/10.3390/cimb45020098 - 9 Feb 2023

Cited by 5 | Viewed by 2722

Abstract

Dementia represents a clinical syndrome characterised by progressive decline in memory, language, visuospatial and executive function, personality, and behaviour, causing loss of abilities to perform instrumental or essential activities of daily living. The most common cause of dementia is Alzheimer’s disease (AD), which accounts for up to 80% of all dementia cases. Despite that extensive studies regarding the etiology and risk factors have been performed in recent decades, and how the current knowledge about AD pathophysiology significantly improved with the recent advances in science and technology, little is still known about its treatment options. In this controverted context, a nutritional approach could be a promising way to formulate improved AD management strategies and to further analyse possible treatment strategy options based on personalised diets, as Nutritional Psychiatry is currently gaining relevance in neuropsychiatric disease treatment. Based on the current knowledge of AD pathophysiology, as well as based on the repeatedly documented anti-inflammatory and antioxidant potential of different functional foods, we aimed to find, describe, and correlate several dietary compounds that could be useful in formulating a nutritional approach in AD management. We performed a screening for relevant studies on the main scientific databases using keywords such as “Alzheimer’s disease”, “dementia”, “treatment”, “medication”, “treatment alternatives”, “vitamin E”, “nutrition”, “selenium”, “Ginkgo biloba”, “antioxidants”, “medicinal plants”, and “traditional medicine” in combinations. Results: nutrients could be a key component in the physiologic and anatomic development of the brain. Several nutrients have been studied in the pursuit of the mechanism triggered by the pathology of AD: vitamin D, fatty acids, selenium, as well as neuroprotective plant extracts (i.e., Ginkgo biloba, Panax ginseng, Curcuma longa), suggesting that the nutritional patterns could modulate the cognitive status and provide neuroprotection. The multifactorial origin of AD development and progression could suggest that nutrition could greatly contribute to the complex pathological picture. The identification of adequate nutritional interventions and the not yet fully understood nutrient activity in AD could be the next steps in finding several innovative treatment options for neurodegenerative disorders. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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17 pages, 1049 KiB

Open AccessReview

The Strategies for Treating “Alzheimer’s Disease”: Insulin Signaling May Be a Feasible Target

by Guanying You, Jinyi Yao, Qiong Liu and Nan Li

Curr. Issues Mol. Biol. 2022, 44(12), 6172-6188; https://doi.org/10.3390/cimb44120421 - 7 Dec 2022

Cited by 6 | Viewed by 2589

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by senile plaques formed by amyloid-beta (Aβ) extracellularly and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein intracellularly. Apart from these two features, insulin deficiency and insulin resistance have also been observed in AD brains. Thus, AD has also been referred to as type 3 diabetes by some of the scientists in this field. Insulin plays a pivotal role in learning and memory and is involved in regulating tau phosphorylation though the PI3KAkt-GSK3b signaling pathway. Interestingly, recent studies revealed that in AD brains the microglia transformed into a disease-associated microglia (DAM) status in a TREM2-dependent manner to restrain the toxicity of Aβ and propagation of tau. This also correlated with PI3K-Akt signaling through the adaptor of TREM2. Whether insulin has any effect on microglia activation in AD pathology is unclear so far. However, many studies demonstrated that diabetes increased the risk of AD. In this review, we summarize the main strategies for curing AD, including lowering the level of Aβ, suppressing the phosphorylation of tau, the ablation and/or repopulation of microglia, and especially the supply of insulin. We also propose that attention should be given to the influences of insulin on microglia in AD. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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32 pages, 1833 KiB

Open AccessReview

Implications of Microorganisms in Alzheimer’s Disease

by Pardeep Yadav, Yeon-Hee Lee, Hrithika Panday, Shubham Kant, Neha Bajwa, Ritika Parashar, Saurabh Kumar Jha, Niraj Kumar Jha, Parma Nand, Sang-Soo Lee and Abhimanyu Kumar Jha

Curr. Issues Mol. Biol. 2022, 44(10), 4584-4615; https://doi.org/10.3390/cimb44100314 - 30 Sep 2022

Cited by 15 | Viewed by 5633

Abstract

Alzheimer’s disease (AD) is a deadly brain degenerative disorder that leads to brain shrinkage and dementia. AD is manifested with hyperphosphorylated tau protein levels and amyloid beta (Aβ) peptide buildup in the hippocampus and cortex regions of the brain. The nervous tissue of AD patients also contains fungal proteins and DNA which are linked to bacterial infections, suggesting that polymicrobial infections also occur in the brains of those with AD. Both immunohistochemistry and next-generation sequencing (NGS) techniques were employed to assess fungal and bacterial infections in the brain tissue of AD patients and non-AD controls, with the most prevalent fungus genera detected in AD patients being Alternaria, Botrytis, Candida, and Malassezia. Interestingly, Fusarium was the most common genus detected in the control group. Both AD patients and controls were also detectable for Proteobacteria, followed by Firmicutes, Actinobacteria, and Bacteroides for bacterial infection. At the family level, Burkholderiaceae and Staphylococcaceae exhibited higher levels in the brains of those with AD than the brains of the control group. Accordingly, there is thought to be a viscous cycle of uncontrolled neuroinflammation and neurodegeneration in the brain, caused by agents such as the herpes simplex virus type 1 (HSV1), Chlamydophilapneumonia, and Spirochetes, and the presence of apolipoprotein E4 (APOE4), which is associated with an increased proinflammatory response in the immune system. Systemic proinflammatory cytokines are produced by microorganisms such as Cytomegalovirus, Helicobacter pylori, and those related to periodontal infections. These can then cross the blood–brain barrier (BBB) and lead to the onset of dementia. Here, we reviewed the relationship between the etiology of AD and microorganisms (such as bacterial pathogens, Herpesviridae viruses, and periodontal pathogens) according to the evidence available to understand the pathogenesis of AD. These findings might guide a targeted anti-inflammatory therapeutic approach to AD. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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Other

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9 pages, 277 KiB

Open AccessBrief Report

Ubiquitin Is Not a Blood Biomarker of an Early Cognitive Decline in the Polish Elderly

by Oliwia McFarlane, Mariusz Kozakiewicz, Milena Wojciechowska and Kornelia Kędziora-Kornatowska

Curr. Issues Mol. Biol. 2023, 45(3), 2452-2460; https://doi.org/10.3390/cimb45030160 - 16 Mar 2023

Cited by 3 | Viewed by 1361

Abstract

Together with development of new pharmaceutical interventions, as well as the introduction of the concept of initial dementia phase, the demand for early diagnosis has been growing. Research on potential blood biomarkers, amazingly attractive, mainly due to the facility of deriving the material, has provided ambiguous results throughout. The existence of an association between ubiquitin and Alzheimer’s disease pathology suggests that it could be a potential neurodegeneration biomarker. The present study aims to identify and assess the relationship between ubiquitin with regard to the adequacy as a biomarker of an initial dementia and cognitive decline in the elderly. Method: The study sample was composed of 230 participants: 109 women and 121 men aged 65 and older. The relationships of plasma ubiquitin levels with cognitive performance, gender, and age were analyzed. The assessments were performed in three groups of cognitive functioning level: cognitively normal, mild cognitive impairment, and mild dementia, of which the subjects were divided with the Mini-Mental State Examination (MMSE). Results: No significant disparities in plasma ubiquitin levels for various levels of cognitive functioning were identified. Significantly higher plasma ubiquitin levels in women were found in comparison to men. No significant differences were found in ubiquitin concentrations based on age. Results suggest that ubiquitin does not meet the requirements for qualification as a blood biomarker of an early cognitive decline. In order to thoroughly evaluate the potential of research on ubiquitin in connection to an early neurodegenerative process, further studies are needed. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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