Alzheimer's Disease: Molecular Mechanisms and Novel Treatment Strategies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: 1 August 2024 | Viewed by 14661

Special Issue Editors


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Guest Editor
1. Department of Cell Biology, Faculty of Sciences, University of Malaga, IBIMA, 29010 Malaga, Spain
2. Networking Research Center on Neurodegenerative Diseases (CIBERNED), 29010 Malaga, Spain
3. Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
Interests: Alzheimer's disease; neurodegeneratrive diseases; amyloid beta; tau; neuroinflammation; risk factors; transgenic animals; preclinical trials

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Guest Editor
Latin American Brain Health Institute (BrainLat), Center for Social and Cognitive Neuroscience (CSCN), Universidad Adolfo Ibanez, Santiago 7941169, Chile
Interests: biomarkers; dementia; neurodegeneration; Tau; amyloid

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Guest Editor
1. LEPABE—Laboratory for Process Engineering, Environment, Biotechnology and Energy, R. Dr. Roberto Frias, 4200-465 Porto, Portugal
2. ALiCE—Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
Interests: nanotechnology and interfacial phenomena; effects of fluorinated systems and peptides on the aggregation of amyloid beta peptides; conformational studies of protein and peptide self-organized systems and polymer surfaces; design and production of inorganic and polymeric nanosystems for pharmaceutical and food applications
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Special Issue Information

Dear Colleagues,

Alzheimer's disease (AD) is the most common form of dementia that accounts for around 50 million cases worldwide. Increasing life expectancy will triple this number by 2050. As long as we remain unable to reverse or prevent AD, its clinical, social, and economic burden will steadily increase hopelessly. The majority of AD cases are sporadic, indicating that the molecular mechanisms that trigger the late onset of the disease are still unknown. Currently, there is no definitive cure for AD, and current clinical interventions help to palliate some clinical symptoms. Prevention and modification of potential risk factors may reduce the probability of developing this type of dementia, but new and more effective therapeutic strategies are needed to prevent, slow down, or even halt the progression of the disease. This Special Issue aims to shed light on the recently described molecular mechanisms that are involved in Alzheimer's pathology, as well as collecting the latest advances in therapeutic interventions to combat this devastating condition.

Dr. Ines Moreno-Gonzalez
Dr. Claudia Duran-Aniotz
Prof. Dr. Joana A. Loureiro
Guest Editors

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Keywords

  • Alzheimer's disease
  • neurodegeneration
  • risk factors
  • therapy

Published Papers (6 papers)

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Research

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27 pages, 5066 KiB  
Article
Neuroprotection of Cholinergic Neurons with a Tau Aggregation Inhibitor and Rivastigmine in an Alzheimer’s-like Tauopathy Mouse Model
by Maciej Zadrozny, Patrycja Drapich, Anna Gasiorowska-Bien, Wiktor Niewiadomski, Charles R. Harrington, Claude M. Wischik, Gernot Riedel and Grazyna Niewiadomska
Cells 2024, 13(7), 642; https://doi.org/10.3390/cells13070642 - 6 Apr 2024
Cited by 1 | Viewed by 896
Abstract
Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer’s disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has [...] Read more.
Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer’s disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. However, its efficacy was diminished in patients already receiving approved acetylcholinesterase inhibitors. In this study, we ask whether this negative interaction can also be mimicked in experimental tau models of AD and whether the underlying mechanism can be understood. From a previous age profiling study, 6-month-old line 1 (L1) tau transgenic mice were characterized by a severe reduction in several cholinergic markers. We therefore assessed whether long-term pre-exposure with the acetylcholinesterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor HMTM can reverse cholinergic deficits in L1. Rivastigmine and HMTM, and combinations of the two compounds were administered orally for 11 weeks to both L1 and wild-type mice. The brains were sectioned with a focus on the basal forebrain, motor cortex and hippocampus. Immunohistochemical staining and quantification of choline acetyltransferase (ChAT), tyrosine kinase A (TrkA)-positive neurons and relative optical intensity (ROI) for vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) reactivity confirmed reversal of the diminished cholinergic phenotype of interneurons (nucleus accumbens, striatum) and projection neurons (medial septum, nucleus basalis magnocellularis) by HMTM, to a greater extent than by rivastigmine alone in L1 mice. Combined administration did not yield additivity but, in most proxies, led to antagonistic effects in which rivastigmine decreased the benefits shown with HMTM alone. Local markers (VAChT and AChE) in target structures of the basal forebrain, motor cortex and hippocampal CA3 seemed to be normalized by HMTM, but not by rivastigmine or the combination of both drugs. HMTM, which was developed as a tau aggregation inhibitor, strongly decreased the tau load in L1 mice, however, not in combination with rivastigmine. Taken together, these data confirm a cholinergic phenotype in L1 tau transgenic mice that resembles the deficits observed in AD patients. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets. Full article
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17 pages, 4865 KiB  
Article
Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease
by Song-I Seol, Dashdulam Davaanyam, Sang-A Oh, Eun-Hwa Lee, Pyung-Lim Han, Seung-Woo Kim and Ja-Kyeong Lee
Cells 2024, 13(2), 189; https://doi.org/10.3390/cells13020189 - 18 Jan 2024
Viewed by 1220
Abstract
HMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer’s disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of HMGB1 in [...] Read more.
HMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer’s disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of HMGB1 in relation to the pathology of Alzheimer’s disease has not yet been studied in detail. Here, we investigated whether HMGB1 protein levels in brain tissue homogenates (frontal cortex and striatum) and sera from Tg-APP/PS1 mice, along with its cellular and subcellular localization in those regions, differed. Total HMGB1 levels were increased in the frontal cortices of aged wildtype (7.5 M) mice compared to young (3.5 M) mice, whereas total HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice (7.5 M) were significantly lower than those in age-matched wildtype mice. In contrast, total serum HMGB1 levels were enhanced in aged wildtype (7.5 M) mice and Tg-APP/PS1 mice (7.5 M). Further analysis indicated that nuclear HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice were significantly reduced compared to those in age-matched wildtype controls, and cytosolic HMGB1 levels were also significantly decreased. Triple-fluorescence immunohistochemical analysis indicated that HMGB1 appeared as a ring shape in the cytoplasm of most neurons and microglia in the frontal cortices of 9.5 M Tg-APP/PS1 mice, indicating that nuclear HMGB1 is reduced by aging and in Tg-APP/PS1 mice. Consistent with these observations, Aβ treatment of both primary cortical neuron and primary microglial cultures increased HMGB1 secretion in the media, in an Aβ-dose-dependent manner. Our results indicate that nuclear HMGB1 might be translocated from the nucleus to the cytoplasm in both neurons and microglia in the brains of Tg-APP/PS1 mice, and that it may subsequently be secreted extracellularly. Full article
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14 pages, 1830 KiB  
Article
Altering Brain Amyloidosis by Intra-Lingual and Extra-Nasal Exposure of Aβ Aggregates
by Nazaret Gamez, Javiera Bravo-Alegria, Yumeng Huang, Nelson Perez-Urrutia, Deepa Dongarwar, Claudio Soto and Rodrigo Morales
Cells 2022, 11(21), 3442; https://doi.org/10.3390/cells11213442 - 31 Oct 2022
Cited by 2 | Viewed by 1654
Abstract
Extensive experimental and human-derived evidence suggest that misfolded Aβ particles spread similarly to infectious prions. Moreover, peripheral administration of Aβ seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aβ from the [...] Read more.
Extensive experimental and human-derived evidence suggest that misfolded Aβ particles spread similarly to infectious prions. Moreover, peripheral administration of Aβ seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aβ from the periphery to the brain are not fully understood, although circulation and retrograde axonal transport have been proposed. Here, we demonstrate that injection of Aβ seeds in the tongue, a highly innervated organ, substantially accelerates the appearance of plaques in Tg2576 mice. In addition, the extra-nasal exposure of Aβ aggregates increased amyloid pathology in the olfactory bulb. Our results show that exposing highly innervated tissues to Aβ seeds accelerates AD-like pathological features, and suggest that Aβ seeds can be transported from peripheral compartments to the brain by retrograde axonal transport. Research in this direction may be relevant on different fronts, including disease mechanisms, diagnosis, and risk-evaluation of potential iatrogenic transmission of Aβ misfolding. Full article
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13 pages, 1429 KiB  
Article
A Method for Bridging Population-Specific Genotypes to Detect Gene Modules Associated with Alzheimer’s Disease
by Yulin Dai, Peilin Jia, Zhongming Zhao and Assaf Gottlieb
Cells 2022, 11(14), 2219; https://doi.org/10.3390/cells11142219 - 16 Jul 2022
Cited by 1 | Viewed by 1938
Abstract
Background: Genome-wide association studies have successfully identified variants associated with multiple conditions. However, generalizing discoveries across diverse populations remains challenging due to large variations in genetic composition. Methods that perform gene expression imputation have attempted to address the transferability of gene discoveries across [...] Read more.
Background: Genome-wide association studies have successfully identified variants associated with multiple conditions. However, generalizing discoveries across diverse populations remains challenging due to large variations in genetic composition. Methods that perform gene expression imputation have attempted to address the transferability of gene discoveries across populations, but with limited success. Methods: Here, we introduce a pipeline that combines gene expression imputation with gene module discovery, including a dense gene module search and a gene set variation analysis, to address the transferability issue. Our method feeds association probabilities of imputed gene expression with a selected phenotype into tissue-specific gene-module discovery over protein interaction networks to create higher-level gene modules. Results: We demonstrate our method’s utility in three case-control studies of Alzheimer’s disease (AD) for three different race/ethnic populations (Whites, African descent and Hispanics). We discovered 182 AD-associated genes from gene modules shared between these populations, highlighting new gene modules associated with AD. Conclusions: Our innovative framework has the potential to identify robust discoveries across populations based on gene modules, as demonstrated in AD. Full article
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14 pages, 989 KiB  
Article
Cerebrospinal Fluid Proteome Alterations Associated with Neuropsychiatric Symptoms in Cognitive Decline and Alzheimer’s Disease
by Magdalena Mroczek, Christopher Clark, Loïc Dayon, Gene L. Bowman and Julius Popp
Cells 2022, 11(6), 1030; https://doi.org/10.3390/cells11061030 - 18 Mar 2022
Cited by 8 | Viewed by 2471
Abstract
Although neuropsychiatric symptoms (NPS) are common and severely affect older people with cognitive decline, little is known about their underlying molecular mechanisms and relationships with Alzheimer’s disease (AD). The aim of this study was to identify and characterize cerebrospinal fluid (CSF) proteome alterations [...] Read more.
Although neuropsychiatric symptoms (NPS) are common and severely affect older people with cognitive decline, little is known about their underlying molecular mechanisms and relationships with Alzheimer’s disease (AD). The aim of this study was to identify and characterize cerebrospinal fluid (CSF) proteome alterations related to NPS. In a longitudinally followed-up cohort of subjects with normal cognition and patients with cognitive impairment (MCI and mild dementia) from a memory clinic setting, we quantified a panel of 790 proteins in CSF using an untargeted shotgun proteomic workflow. Regression models and pathway enrichment analysis were used to investigate protein alterations related to NPS, and to explore relationships with AD pathology and cognitive decline at follow-up visits. Regression analysis selected 27 CSF proteins associated with NPS. These associations were independent of the presence of cerebral AD pathology (defined as CSF p-tau181/Aβ1–42 > 0.0779, center cutoff). Gene ontology enrichment showed abundance alterations of proteins related to cell adhesion, immune response, and lipid metabolism, among others, in relation to NPS. Out of the selected proteins, three were associated with accelerated cognitive decline at follow-up visits after controlling for possible confounders. Specific CSF proteome alterations underlying NPS may both represent pathophysiological processes independent from AD and accelerate clinical disease progression. Full article
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Review

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22 pages, 799 KiB  
Review
New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer’s Disease and Its Potential for Therapeutic Intervention
by Tiantian Li, Li Lu, Eloise Pember, Xinuo Li, Bocheng Zhang and Zheying Zhu
Cells 2022, 11(12), 1925; https://doi.org/10.3390/cells11121925 - 14 Jun 2022
Cited by 32 | Viewed by 4979
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics solely focus on symptomatic management instead of preventative or curative strategies. The two most widely accepted pathogenic mechanisms of AD include the amyloid and tau hypotheses. However, it is evident that these hypotheses cannot fully explain neuronal degeneration shown in AD. Substantial evidence is growing for the vital role of neuroinflammation in AD pathology. The neuroinflammatory hypothesis provides a new, exciting lead in uncovering the underlying mechanisms contributing to AD. This review aims to highlight new insights into the role of neuroinflammation in the pathogenesis of AD, mainly including the involvement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed on myeloid cells 2 (TREM2) and cGAS-STING as key influencers in augmenting AD development. The inflammasomes related to the pathways of NF-κB, NLRP3, TREM2, and cGAS-STING as biomarkers of the neuroinflammation associated with AD, as well as an overview of novel AD treatments based on these biomarkers as potential drug targets reported in the literature or under clinical trials, are explored. Full article
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