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10 pages, 1910 KiB

Open AccessArticle

Tau Lysine Pseudomethylation Regulates Microtubule Binding and Enhances Prion-like Tau Aggregation

by Yuxing Xia, Brach M. Bell and Benoit I. Giasson

Int. J. Mol. Sci. 2023, 24(9), 8286; https://doi.org/10.3390/ijms24098286 - 5 May 2023

Cited by 4 | Viewed by 2039

Abstract

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by various post-translational modifications (PTMs) that include phosphorylation, acetylation, [...] Read more.

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by various post-translational modifications (PTMs) that include phosphorylation, acetylation, and methylation. Tau methylation has emerged as a target of interest for its potential involvement in tau pathomechanisms. Filamentous tau aggregates isolated from patients with AD are methylated at multiple lysine residues, although the exact methyltransferases have not been identified. One strategy to study the site-specific effects of methylation is to create methylation mimetics using a KFC model, which replaces lysine (K) with a hydrophobic group such as phenylalanine (F) to approximate the effects of lysine methylation (C or methyl group). In this study, tau methylmimetics were used to model several functional aspects of tau methylation such as effects on microtubule binding and tau aggregation in cell models. Overall, several tau methylmimetics displayed impaired microtubule binding, and tau methylmimetics enhanced prion-like seeded aggregation in the context of the FTD tau mutation P301L. Like other PTMs, tau methylation is a contributing factor to tau pathogenesis and could be a potential therapeutic drug target for the treatment of different tauopathies. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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7 pages, 6406 KiB

Open AccessCommunication

Double Mutations in a Patient with Early-Onset Alzheimer’s Disease in Korea: An APP Val551Met and a PSEN2 His169Asn

by Heewon Bae, Kyu Hwan Shim, Jang Yoo, Young-Soon Yang, Seong Soo A. An and Min-Ju Kang

Int. J. Mol. Sci. 2023, 24(8), 7446; https://doi.org/10.3390/ijms24087446 - 18 Apr 2023

Viewed by 1258

Abstract

The etiology of early-onset Alzheimer’s disease (EOAD) is associated with alterations in the production of amyloid beta (Aβ) species caused by mutations in the APP, PSEN1, and PSEN2 genes. Mutations affect intra- or inter-molecular interactions and processes between the γ-secretase complex [...] Read more.

The etiology of early-onset Alzheimer’s disease (EOAD) is associated with alterations in the production of amyloid beta (Aβ) species caused by mutations in the APP, PSEN1, and PSEN2 genes. Mutations affect intra- or inter-molecular interactions and processes between the γ-secretase complex and amyloid precursor protein (APP), leading to the aberrant sequential cleavage of Aβ species. A 64-year-old woman presented with progressive memory decline, mild right hippocampal atrophy, and a family history of Alzheimer’s dementia (AD). Whole exome sequencing was performed to evaluate AD-related gene mutations, which were verified by Sanger sequencing. A mutation-caused structural alteration of APP was predicted using in silico prediction programs. Two AD-related mutations, in APP (rs761339914; c.G1651A; p.V551M) and PSEN2 (rs533813519; c.C505A; p.H169N), were identified. The APP Val551Met mutation in the E2 domain may influence APP homodimerization through changes in intramolecular interactions between adjacent amino acids, altering Aβ production. The second mutation was PSEN2 His169Asn mutation, which was previously reported in five EOAD patients from Korea and China, with a relatively high frequency in the East Asian population. According to a previous report, the presenilin 2 protein was predicted to result in a major helical torsion by PSEN2 His169Asn mutation. Notably, the co-existence of APP Val551Met and PSEN2 His169Asn may induce a synergistic effect by both mutations. Future functional studies are needed to clarify the pathological effects of these double mutations. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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21 pages, 5852 KiB

Open AccessArticle

Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease

by Xin Tun, Evan J. Wang, Zhenxiang Gao, Kathleen Lundberg, Rong Xu and Di Hu

Int. J. Mol. Sci. 2023, 24(6), 5697; https://doi.org/10.3390/ijms24065697 - 16 Mar 2023

Cited by 6 | Viewed by 2142

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes that ultimately lead to dementia. Currently, 50 million people worldwide suffer from dementia related to AD, and the pathogenesis underlying AD pathology and cognitive decline is unknown. While AD [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes that ultimately lead to dementia. Currently, 50 million people worldwide suffer from dementia related to AD, and the pathogenesis underlying AD pathology and cognitive decline is unknown. While AD is primarily a neurological disease of the brain, individuals with AD often experience intestinal disorders, and gut abnormalities have been implicated as a major risk factor in the development of AD and relevant dementia. However, the mechanisms that mediate gut injury and contribute to the vicious cycle between gut abnormalities and brain injury in AD remain unknown. In the present study, a bioinformatics analysis was performed on the proteomics data of variously aged AD mouse colon tissues. We found that levels of integrin β3 and β-galactosidase (β-gal), two markers of cellular senescence, increased with age in the colonic tissue of mice with AD. The advanced artificial intelligence (AI)-based prediction of AD risk also demonstrated the association between integrin β3 and β-gal and AD phenotypes. Moreover, we showed that elevated integrin β3 levels were accompanied by senescence phenotypes and immune cell accumulation in AD mouse colonic tissue. Further, integrin β3 genetic downregulation abolished upregulated senescence markers and inflammatory responses in colonic epithelial cells in conditions associated with AD. We provide a new understanding of the molecular actions underpinning inflammatory responses during AD and suggest integrin β3 may function as novel target mediating gut abnormalities in this disease. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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Review

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20 pages, 2253 KiB

Open AccessReview

Microglial Transforming Growth Factor-β Signaling in Alzheimer’s Disease

by Natascha Vidovic and Björn Spittau

Int. J. Mol. Sci. 2024, 25(6), 3090; https://doi.org/10.3390/ijms25063090 - 7 Mar 2024

Cited by 3 | Viewed by 2081

Abstract

Novel technologies such as single-cell RNA and single-nucleus RNA sequencing have shed new light on the complexity of different microglia populations in physiological and pathological states. The transcriptomic profiling of these populations has led to the subclassification of specific disease-associated microglia and microglia [...] Read more.

Novel technologies such as single-cell RNA and single-nucleus RNA sequencing have shed new light on the complexity of different microglia populations in physiological and pathological states. The transcriptomic profiling of these populations has led to the subclassification of specific disease-associated microglia and microglia clusters in neurodegenerative diseases. A common profile includes the downregulation of homeostasis and the upregulation of inflammatory markers. Furthermore, there is concordance in few clusters between murine and human samples. Apolipoprotein E, which has long been considered a high-risk factor for late-onset Alzheimer’s disease, is strongly regulated in both these murine and human clusters. Transforming growth factor-β plays an essential role during the development and maturation of microglia. In a pathological state, it attenuates their activation and is involved in numerous cell regulatory processes. Transforming growth factor-β also has an influence on the deposition of amyloid-beta, as it is involved in the regulation of key proteins and molecules. Taken together, this review highlights the complex interaction of apolipoprotein E, the triggering receptor on myeloid cells 2, and transforming growth factor-β as part of a regulatory axis in microglia at the onset and over the course of Alzheimer’s disease. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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29 pages, 2355 KiB

Open AccessReview

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

by Erin G. Reed and Phaedra R. Keller-Norrell

Int. J. Mol. Sci. 2023, 24(24), 17377; https://doi.org/10.3390/ijms242417377 - 12 Dec 2023

Cited by 3 | Viewed by 2013

Abstract

Research into Alzheimer’s Disease (AD) describes a link between AD and the resident immune cells of the brain, the microglia. Further, this suspected link is thought to have underlying sex effects, although the mechanisms of these effects are only just beginning to be [...] Read more.

Research into Alzheimer’s Disease (AD) describes a link between AD and the resident immune cells of the brain, the microglia. Further, this suspected link is thought to have underlying sex effects, although the mechanisms of these effects are only just beginning to be understood. Many of these insights are the result of policies put in place by funding agencies such as the National Institutes of Health (NIH) to consider sex as a biological variable (SABV) and the move towards precision medicine due to continued lackluster therapeutic options. The purpose of this review is to provide an updated assessment of the current research that summarizes sex differences and the research pertaining to microglia and their varied responses in AD. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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18 pages, 1627 KiB

Open AccessReview

The Role of Insulin-like Growth Factor I in Mechanisms of Resilience and Vulnerability to Sporadic Alzheimer’s Disease

by Jonathan A. Zegarra-Valdivia, Jaime Pignatelli, Angel Nuñez and Ignacio Torres Aleman

Int. J. Mol. Sci. 2023, 24(22), 16440; https://doi.org/10.3390/ijms242216440 - 17 Nov 2023

Cited by 4 | Viewed by 1681

Abstract

Despite decades of intense research, disease-modifying therapeutic approaches for Alzheimer’s disease (AD) are still very much needed. Apart from the extensively analyzed tau and amyloid pathological cascades, two promising avenues of research that may eventually identify new druggable targets for AD are based [...] Read more.

Despite decades of intense research, disease-modifying therapeutic approaches for Alzheimer’s disease (AD) are still very much needed. Apart from the extensively analyzed tau and amyloid pathological cascades, two promising avenues of research that may eventually identify new druggable targets for AD are based on a better understanding of the mechanisms of resilience and vulnerability to this condition. We argue that insulin-like growth factor I (IGF-I) activity in the brain provides a common substrate for the mechanisms of resilience and vulnerability to AD. We postulate that preserved brain IGF-I activity contributes to resilience to AD pathology as this growth factor intervenes in all the major pathological cascades considered to be involved in AD, including metabolic impairment, altered proteostasis, and inflammation, to name the three that are considered to be the most important ones. Conversely, disturbed IGF-I activity is found in many AD risk factors, such as old age, type 2 diabetes, imbalanced diet, sedentary life, sociality, stroke, stress, and low education, whereas the Apolipoprotein (Apo) E4 genotype and traumatic brain injury may also be influenced by brain IGF-I activity. Accordingly, IGF-I activity should be taken into consideration when analyzing these processes, while its preservation will predictably help prevent the progress of AD pathology. Thus, we need to define IGF-I activity in all these conditions and develop a means to preserve it. However, defining brain IGF-I activity cannot be solely based on humoral or tissue levels of this neurotrophic factor, and new functionally based assessments need to be developed. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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22 pages, 2971 KiB

Open AccessReview

Phototherapy of Alzheimer’s Disease: Photostimulation of Brain Lymphatics during Sleep: A Systematic Review

by Oxana Semyachkina-Glushkovskaya, Thomas Penzel, Mikhail Poluektov, Ivan Fedosov, Maria Tzoy, Andrey Terskov, Inna Blokhina, Viktor Sidorov and Jürgen Kurths

Int. J. Mol. Sci. 2023, 24(13), 10946; https://doi.org/10.3390/ijms241310946 - 30 Jun 2023

Cited by 10 | Viewed by 2852

Abstract

The global number of people with Alzheimer’s disease (AD) doubles every 5 years. It has been established that unless an effective treatment for AD is found, the incidence of AD will triple by 2060. However, pharmacological therapies for AD have failed to show [...] Read more.

The global number of people with Alzheimer’s disease (AD) doubles every 5 years. It has been established that unless an effective treatment for AD is found, the incidence of AD will triple by 2060. However, pharmacological therapies for AD have failed to show effectiveness and safety. Therefore, the search for alternative methods for treating AD is an urgent problem in medicine. The lymphatic drainage and removal system of the brain (LDRSB) plays an important role in resistance to the progression of AD. The development of methods for augmentation of the LDRSB functions may contribute to progress in AD therapy. Photobiomodulation (PBM) is considered to be a non-pharmacological and safe approach for AD therapy. Here, we highlight the most recent and relevant studies of PBM for AD. We focus on emerging evidence that indicates the potential benefits of PBM during sleep for modulation of natural activation of the LDRSB at nighttime, providing effective removal of metabolites, including amyloid-β, from the brain, leading to reduced progression of AD. Our review creates a new niche in the therapy of brain diseases during sleep and sheds light on the development of smart sleep technologies for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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27 pages, 1478 KiB

Open AccessReview

Roles of Rac1-Dependent Intrinsic Forgetting in Memory-Related Brain Disorders: Demon or Angel

by Wei Wang, Zixu Wang, Jing Cao, Yulan Dong and Yaoxing Chen

Int. J. Mol. Sci. 2023, 24(13), 10736; https://doi.org/10.3390/ijms241310736 - 27 Jun 2023

Cited by 3 | Viewed by 2924

Abstract

Animals are required to handle daily massive amounts of information in an ever-changing environment, and the resulting memories and experiences determine their survival and development, which is critical for adaptive evolution. However, intrinsic forgetting, which actively deletes irrelevant information, is equally important for [...] Read more.

Animals are required to handle daily massive amounts of information in an ever-changing environment, and the resulting memories and experiences determine their survival and development, which is critical for adaptive evolution. However, intrinsic forgetting, which actively deletes irrelevant information, is equally important for memory acquisition and consolidation. Recently, it has been shown that Rac1 activity plays a key role in intrinsic forgetting, maintaining the balance of the brain’s memory management system in a controlled manner. In addition, dysfunctions of Rac1-dependent intrinsic forgetting may contribute to memory deficits in neurological and neurodegenerative diseases. Here, these new findings will provide insights into the neurobiology of memory and forgetting, pathological mechanisms and potential therapies for brain disorders that alter intrinsic forgetting mechanisms. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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42 pages, 2188 KiB

Open AccessReview

Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer’s Disease

by Daniela Baracaldo-Santamaría, Sara Sofia Avendaño-Lopez, Daniel Felipe Ariza-Salamanca, Mateo Rodriguez-Giraldo, Carlos A. Calderon-Ospina, Rodrigo E. González-Reyes and Mauricio O. Nava-Mesa

Int. J. Mol. Sci. 2023, 24(10), 9067; https://doi.org/10.3390/ijms24109067 - 22 May 2023

Cited by 24 | Viewed by 4662

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most frequent cause of progressive dementia in senior adults. It is characterized by memory loss and cognitive impairment secondary to cholinergic dysfunction and N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed of [...] Read more.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most frequent cause of progressive dementia in senior adults. It is characterized by memory loss and cognitive impairment secondary to cholinergic dysfunction and N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed of amyloid-β (Aβ), and selective neurodegeneration are the anatomopathological hallmarks of this disease. The dysregulation of calcium may be present in all the stages of AD, and it is associated with other pathophysiological mechanisms, such as mitochondrial failure, oxidative stress, and chronic neuroinflammation. Although the cytosolic calcium alterations in AD are not completely elucidated, some calcium-permeable channels, transporters, pumps, and receptors have been shown to be involved at the neuronal and glial levels. In particular, the relationship between glutamatergic NMDA receptor (NMDAR) activity and amyloidosis has been widely documented. Other pathophysiological mechanisms involved in calcium dyshomeostasis include the activation of L-type voltage-dependent calcium channels, transient receptor potential channels, and ryanodine receptors, among many others. This review aims to update the calcium-dysregulation mechanisms in AD and discuss targets and molecules with therapeutic potential based on their modulation. Full article

(This article belongs to the Special Issue Recent Advances in Alzheimer’s Disease)

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