Editorial

7 pages, 239 KiB

Open AccessEditorial

Special Issue “Alzheimer’s Disease—115 Years after Its Discovery”

by Susana Cardoso, Cristina Carvalho and Sónia C. Correia

Biomedicines 2024, 12(3), 478; https://doi.org/10.3390/biomedicines12030478 - 21 Feb 2024

Viewed by 574

Alzheimer’s disease (AD) is a progressive and multifactorial disease that significantly compromises the lives of millions of people worldwide [...] Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

Research

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16 pages, 4124 KiB

Open AccessArticle

Hybridized Deep Learning Approach for Detecting Alzheimer’s Disease

by Prasanalakshmi Balaji, Mousmi Ajay Chaurasia, Syeda Meraj Bilfaqih, Anandhavalli Muniasamy and Linda Elzubir Gasm Alsid

Biomedicines 2023, 11(1), 149; https://doi.org/10.3390/biomedicines11010149 - 06 Jan 2023

Cited by 19 | Viewed by 4637

Abstract

Alzheimer’s disease (AD) is mainly a neurodegenerative sickness. The primary characteristics are neuronal atrophy, amyloid deposition, and cognitive, behavioral, and psychiatric disorders. Numerous machine learning (ML) algorithms have been investigated and applied to AD identification over the past decades, emphasizing the subtle prodromal [...] Read more.

Alzheimer’s disease (AD) is mainly a neurodegenerative sickness. The primary characteristics are neuronal atrophy, amyloid deposition, and cognitive, behavioral, and psychiatric disorders. Numerous machine learning (ML) algorithms have been investigated and applied to AD identification over the past decades, emphasizing the subtle prodromal stage of mild cognitive impairment (MCI) to assess critical features that distinguish the disease’s early manifestation and instruction for early detection and treatment. Identifying early MCI (EMCI) remains challenging due to the difficulty in distinguishing patients with cognitive normality from those with MCI. As a result, most classification algorithms for these two groups perform poorly. This paper proposes a hybrid Deep Learning Approach for the early detection of Alzheimer’s disease. A method for early AD detection using multimodal imaging and Convolutional Neural Network with the Long Short-term memory algorithm combines magnetic resonance imaging (MRI), positron emission tomography (PET), and standard neuropsychological test scores. The proposed methodology updates the learning weights, and Adam’s optimization is used to increase accuracy. The system has an unparalleled accuracy of 98.5% in classifying cognitively normal controls from EMCI. These results imply that deep neural networks may be trained to automatically discover imaging biomarkers indicative of AD and use them to identify the illness accurately. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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19 pages, 4506 KiB

Open AccessArticle

Progressive Vascular Abnormalities in the Aging 3xTg-AD Mouse Model of Alzheimer’s Disease

by Amandine Jullienne, Ryan Quan, Jenny I. Szu, Michelle V. Trinh, Erik J. Behringer and Andre Obenaus

Biomedicines 2022, 10(8), 1967; https://doi.org/10.3390/biomedicines10081967 - 13 Aug 2022

Cited by 10 | Viewed by 2112

Abstract

Vascular dysfunction and structural abnormalities in Alzheimer’s disease (AD) are known to contribute to the progression of the pathology, and studies have tended to ignore the role of the vasculature in AD progression. We utilized the 3xTg-AD mouse model of AD to examine [...] Read more.

Vascular dysfunction and structural abnormalities in Alzheimer’s disease (AD) are known to contribute to the progression of the pathology, and studies have tended to ignore the role of the vasculature in AD progression. We utilized the 3xTg-AD mouse model of AD to examine individual cerebral vessels and the cortical vascular network across the lifespan. Our vessel painting approach was used to label the entire cortical vasculature, followed by epifluorescence microscopy. The middle cerebral artery (MCA) tree was assessed with confocal microscopy, and a new method was developed to assess branching patterns as a measure of aging-related changes. We found that vascular remodeling was profoundly altered at 4–6 months of age, when the 3xTg-AD mouse is known to transition to cognitive impairment and Aβ deposition in both sexes. Analysis of vascular features (density, junctions, length) of the MCA territory highlighted sex-dependent differences across the 3xTg-AD mouse lifespan, with no alterations in branching patterns. Our current cerebrovascular angioarchitectural analyses demonstrate progressive alterations in individual cortical vessels, as well as in the vascular network of the cortex. These new findings advance our understanding of brain anatomy and physiology in the 3xTg-AD mouse, while potentially identifying unique diagnostic signatures of AD progression. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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51 pages, 13524 KiB

Open AccessEditor’s ChoiceArticle

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

by How-Wing Leung, Gabriel Foo and Antonius VanDongen

Biomedicines 2022, 10(8), 1946; https://doi.org/10.3390/biomedicines10081946 - 11 Aug 2022

Cited by 12 | Viewed by 4602

Abstract

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal [...] Read more.

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Both these histone modifications, H3K27Ac and H3K9Ac, have recently been shown to be upregulated in late-onset Alzheimer’s disease (AD). When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes, which included genes associated with synaptic function, neuronal plasticity, intrinsic excitability, and signalling pathways. Interestingly, about 100 Arc-dependent genes are associated with the pathophysiology of AD. When endogenous Arc expression was induced in HEK293T cells, the transcription of many neuronal genes was increased, suggesting that Arc can control expression in the absence of activated signalling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and suggest that it plays a significant role in the pathophysiology of AD. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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16 pages, 2269 KiB

Open AccessArticle

Differentially Aquaporin 5 Expression in Submandibular Glands and Cerebral Cortex in Alzheimer’s Disease

by Desiree Antequera, Laura Carrero, Victoria Cunha Alves, Isidro Ferrer, Jesús Hernández-Gallego, Cristina Municio and Eva Carro

Biomedicines 2022, 10(7), 1645; https://doi.org/10.3390/biomedicines10071645 - 08 Jul 2022

Cited by 4 | Viewed by 1675

Abstract

Impaired brain clearance mechanisms may result in the accumulation of aberrant proteins that define Alzheimer’s disease (AD). The water channel protein astrocytic aquaporin 4 (AQP4) is essential for brain amyloid-β clearance, but it is known to be abnormally expressed in AD brains. The [...] Read more.

Impaired brain clearance mechanisms may result in the accumulation of aberrant proteins that define Alzheimer’s disease (AD). The water channel protein astrocytic aquaporin 4 (AQP4) is essential for brain amyloid-β clearance, but it is known to be abnormally expressed in AD brains. The expression of AQPs is differentially regulated during diverse brain injuries, but, whereas AQP4 expression and function have been studied in AD, less is known about AQP5. AQP5 functions include not only water transport but also cell migration mediated by cytoskeleton regulation. Moreover, AQP5 has been reported to be expressed in astrocytes, which are regulated after ischemic and traumatic injury. Additionally, AQP5 is particularly abundant in the salivary glands suggesting that it may be a crucial factor in gland dysfunction associated with AD. Herein, we aim to determine whether AQP5 expression in submandibular glands and the brain was altered in AD. First, we demonstrated impaired AQP5 expression in submandibular glands in APP/PS1 mice and AD patients. Subsequently, we observed that AQP5 expression was upregulated in APP/PS1 cerebral cortex and confirmed its expression both in astrocytes and neurons. Our findings propose AQP5 as a significant role player in AD pathology, in addition to AQP4, representing a potential target for the treatment of AD. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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27 pages, 5019 KiB

Open AccessArticle

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer’s Disease

by David Vicente-Zurdo, Noelia Rosales-Conrado, M. Eugenia León-González, Leonardo Brunetti, Luca Piemontese, A. Raquel Pereira-Santos, Sandra M. Cardoso, Yolanda Madrid, Sílvia Chaves and M. Amélia Santos

Biomedicines 2022, 10(7), 1510; https://doi.org/10.3390/biomedicines10071510 - 26 Jun 2022

Cited by 14 | Viewed by 2980

Abstract

Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the [...] Read more.

Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ₄₂ aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC₅₀ = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC₅₀ = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ₄₂ and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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15 pages, 1399 KiB

Open AccessArticle

High-Density Lipoprotein Changes in Alzheimer’s Disease Are APOE Genotype-Specific

by Brian V. Hong, Jingyuan Zheng, Joanne K. Agus, Xinyu Tang, Carlito B. Lebrilla, Lee-Way Jin, Izumi Maezawa, Kelsey Erickson, Danielle J. Harvey, Charles S. DeCarli, Dan M. Mungas, John M. Olichney, Sarah T. Farias and Angela M. Zivkovic

Biomedicines 2022, 10(7), 1495; https://doi.org/10.3390/biomedicines10071495 - 24 Jun 2022

Cited by 6 | Viewed by 2475

Abstract

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and [...] Read more.

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer’s disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer’s disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer’s disease and an association between HDL function, size, and cognitive function. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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19 pages, 3047 KiB

Open AccessArticle

Amyloid Beta Oligomers-Induced Ca²⁺ Entry Pathways: Role of Neuronal Networks, NMDA Receptors and Amyloid Channel Formation

by Erica Caballero, Elena Hernando-Pérez, Victor Tapias, María Calvo-Rodríguez, Carlos Villalobos and Lucía Núñez

Biomedicines 2022, 10(5), 1153; https://doi.org/10.3390/biomedicines10051153 - 17 May 2022

Cited by 8 | Viewed by 1800

Abstract

The molecular basis of amyloid toxicity in Alzheimer’s disease (AD) remains controversial. Amyloid β (Aβ) oligomers promote Ca²⁺ influx, mitochondrial Ca²⁺ overload and apoptosis in hippocampal neurons in vivo and in vitro, but the primary Ca²⁺ entry pathways are unclear. [...] Read more.

The molecular basis of amyloid toxicity in Alzheimer’s disease (AD) remains controversial. Amyloid β (Aβ) oligomers promote Ca²⁺ influx, mitochondrial Ca²⁺ overload and apoptosis in hippocampal neurons in vivo and in vitro, but the primary Ca²⁺ entry pathways are unclear. We studied Ca²⁺ entry pathways induced by Aβ oligomers in rat hippocampal and cerebellar neurons. Aβ oligomers induce Ca²⁺ entry in neurons. Ca²⁺ responses to Aβ oligomers are large after synaptic networking and prevented by blockers of synaptic transmission. In contrast, in neurons devoid of synaptic connections, Ca²⁺ responses to Aβ oligomers are small and prevented only by blockers of amyloid channels (NA7) and NMDA receptors (MK801). A combination of NA7 and MK801 nearly abolished Ca²⁺ responses. Non-neuronal cells bearing NMDA receptors showed Ca²⁺ responses to oligomers, whereas cells without NMDA receptors did not exhibit Ca²⁺ responses. The expression of subunits of the NMDA receptor NR1/ NR2A and NR1/NR2B in HEK293 cells lacking endogenous NMDA receptors restored Ca²⁺ responses to NMDA but not to Aβ oligomers. We conclude that Aβ oligomers promote Ca²⁺ entry via amyloid channels and NMDA receptors. This may recruit distant neurons intertwisted by synaptic connections, spreading excitation and recruiting further NMDA receptors and voltage-gated Ca²⁺ channels, leading to excitotoxicity and neuron degeneration in AD. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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13 pages, 4328 KiB

Open AccessArticle

Nasal Rifampicin Halts the Progression of Tauopathy by Inhibiting Tau Oligomer Propagation in Alzheimer Brain Extract-Injected Mice

by Tomohiro Umeda, Rumi Uekado, Keiko Shigemori, Hiroshi Eguchi and Takami Tomiyama

Biomedicines 2022, 10(2), 297; https://doi.org/10.3390/biomedicines10020297 - 27 Jan 2022

Cited by 9 | Viewed by 3203

Abstract

The cell-to-cell transmission of tau aggregates is considered a mechanism underlying the intracerebral spreading of tau pathology in Alzheimer’s disease (AD) and other tauopathies. Recent studies suggest that tau oligomers, rather than fibrils, participate in this process. We previously showed that intranasal rifampicin [...] Read more.

The cell-to-cell transmission of tau aggregates is considered a mechanism underlying the intracerebral spreading of tau pathology in Alzheimer’s disease (AD) and other tauopathies. Recent studies suggest that tau oligomers, rather than fibrils, participate in this process. We previously showed that intranasal rifampicin inhibits tau oligomer accumulation and improves cognition in tauopathy mice. In the present study, we examined the effects of nasal rifampicin on tau propagation in a new mouse model of tauopathy. A tau oligomer-rich fraction prepared from the brain of an AD patient was injected into a unilateral hippocampus of tau264 mice that express both 3-repeat and 4-repeat wild-type human tau. Rifampicin administration was started one week after the injection and performed three times a week for 24 weeks. Cognitive function and tau pathology were assessed by the Morris water maze test and brain section staining. Rifampicin treatment inhibited the spreading of tau oligomers from the injection site to other brain regions and neurofibrillary tangle formation in the entorhinal cortex. Synapse and neuronal loss in the hippocampus were also prevented, and cognitive function remained normal. These results suggest that intranasal rifampicin could be a promising remedy that halts the progression of tauopathy by inhibiting tau oligomer propagation. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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10 pages, 1878 KiB

Open AccessArticle

Fluorescent Aptasensor and Colorimetric Aptablot for p-tau231 Detection: Toward Early Diagnosis of Alzheimer’s Disease

by Le Minh Tu Phan and Sungbo Cho

Biomedicines 2022, 10(1), 93; https://doi.org/10.3390/biomedicines10010093 - 01 Jan 2022

Cited by 6 | Viewed by 2583

Abstract

The pathology of Alzheimer’s disease (AD), the most common cause of dementia, is considered to be mainly driven by two major hallmarks (tau and amyloid beta). It is highly desirable to develop an affordable medicinal diagnostic that can be utilized worldwide for the [...] Read more.

The pathology of Alzheimer’s disease (AD), the most common cause of dementia, is considered to be mainly driven by two major hallmarks (tau and amyloid beta). It is highly desirable to develop an affordable medicinal diagnostic that can be utilized worldwide for the early diagnosis of AD. Hence, p-tau231 was selected as a specific target, which appears both in AD serum and cerebrospinal fluid, for the development of a sensing platform for the diagnosis of AD. To the best of our knowledge, these are the first aptamer-mediated biosensors that rely on sensitive fluorescent and colorimetric aptasensors for the rapid monitoring of p-tau231. The nitrogen-doped carbon dot-based turn-on fluorescent aptasensor could rapidly analyze p-tau231 down to 3.64 ng/mL within 40 min, and the colorimetric Cu-enhanced-Au aptablot displayed high sensitivity at 4.71 pg/mL through a digital camera, with visibility to the naked eye down to 8 ng/mL p-tau231 within 140 min. Owing to their advantages, which include affordability, rapidity, high sensitivity, and dependence on complicated instruments, these aptamer-based biosensors offer significant potential for the early diagnosis of AD worldwide. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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21 pages, 3785 KiB

Open AccessArticle

Identification of Disease-Related Genes That Are Common between Alzheimer’s and Cardiovascular Disease Using Blood Genome-Wide Transcriptome Analysis

by Taesic Lee, Hyunju Lee and the Alzheimer’s Disease Neuroimaging Initiative

Biomedicines 2021, 9(11), 1525; https://doi.org/10.3390/biomedicines9111525 - 23 Oct 2021

Cited by 11 | Viewed by 2613

Abstract

Accumulating evidence has suggested a shared pathophysiology between Alzheimer’s disease (AD) and cardiovascular disease (CVD). Based on genome-wide transcriptomes, specifically those of blood samples, we identify the shared disease-related signatures between AD and CVD. In addition to gene expressions in blood, the following [...] Read more.

Accumulating evidence has suggested a shared pathophysiology between Alzheimer’s disease (AD) and cardiovascular disease (CVD). Based on genome-wide transcriptomes, specifically those of blood samples, we identify the shared disease-related signatures between AD and CVD. In addition to gene expressions in blood, the following prior knowledge were utilized to identify several candidate disease-related gene (DRG) sets: protein–protein interactions, transcription factors, disease–gene relationship databases, and single nucleotide polymorphisms. We selected the respective DRG sets for AD and CVD that show a high accuracy for disease prediction in bulk and single-cell gene expression datasets. Then, gene regulatory networks (GRNs) were constructed from each of the AD and CVD DRG sets to identify the upstream regulating genes. Using the GRNs, we identified two common upstream genes (GPBP1 and SETDB2) between the AD and CVD GRNs. In summary, this study has identified the potential AD- and CVD-related genes and common hub genes between these sets, which may help to elucidate the shared mechanisms between these two diseases. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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9 pages, 728 KiB

Open AccessArticle

ReCODE: A Personalized, Targeted, Multi-Factorial Therapeutic Program for Reversal of Cognitive Decline

by Rammohan V Rao, Sharanya Kumar, Julie Gregory, Christine Coward, Sho Okada, William Lipa, Lance Kelly and Dale E Bredesen

Biomedicines 2021, 9(10), 1348; https://doi.org/10.3390/biomedicines9101348 - 29 Sep 2021

Cited by 12 | Viewed by 7950

Abstract

Background: Alzheimer’s disease (AD) is the major cause of age-associated cognitive decline, and in the absence of effective therapeutics is progressive and ultimately fatal, creating a dire need for successful prevention and treatment strategies. We recently reported results of a successful proof-of-concept trial, [...] Read more.

Background: Alzheimer’s disease (AD) is the major cause of age-associated cognitive decline, and in the absence of effective therapeutics is progressive and ultimately fatal, creating a dire need for successful prevention and treatment strategies. We recently reported results of a successful proof-of-concept trial, using a personalized, precision medicine protocol, but whether such an approach is readily scalable is unknown. Objective: In the case of AD, there is not a single therapeutic that exerts anything beyond a marginal, unsustained, symptomatic effect. This suggests that the monotherapeutic approach of drug development for AD may not be an optimal one, at least when used alone. Using a novel, comprehensive, and personalized therapeutic system called ReCODE (reversal of cognitive decline), which proved successful in a small, proof-of-concept trial, we sought to determine whether the program could be scaled to improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early-stage AD. Methods: 255 individuals submitted blood samples, took the Montreal Cognitive Assessment (MoCA) test, and answered intake questions. Individuals who enrolled in the ReCODE program had consultations with clinical practitioners, and explanations of the program were provided. Participants had follow-up visits that included education regarding diet, lifestyle choices, medications, supplements, repeat blood sample analysis, and MoCA testing between 2 and 12 months after participating in the ReCODE program. Pre- and post-treatment measures were compared using the non-parametric Wilcoxon signed rank test. Results and Conclusions: By comparing baseline to follow-up testing, we observed that MoCA scores either significantly improved or stabilized in the entire participant pool—results that were not as successful as those in the proof-of-concept trial, but more successful than anti-amyloid therapies—and other risk factors including blood glucose, high-sensitivity C-reactive protein, HOMA-IR, and vitamin D significantly improved in the participant pool. Our findings provide evidence that a multi-factorial, comprehensive, and personalized therapeutic program designed to mitigate AD risk factors can improve risk factor scores and stabilize or reverse the decline in cognitive function. Since superior results were obtained in the proof-of-concept trial, which was conducted by a small group of highly trained and experienced physicians, it is possible that results from the use of this personalized approach would be enhanced by further training and experience of the practicing physicians. Nonetheless, the current results provide further support indicating the potential of such an approach for the prevention and reversal of cognitive decline. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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16 pages, 752 KiB

Open AccessArticle

Fine Tuning of Cholinesterase and Glutathione-S-Transferase Activities by Organoruthenium(II) Complexes

by Tomaž Trobec, Kristina Sepčić, Monika Cecilija Žužek, Jerneja Kladnik, Nina Podjed, Catarina Cardoso Páscoa, Iztok Turel and Robert Frangež

Biomedicines 2021, 9(9), 1243; https://doi.org/10.3390/biomedicines9091243 - 16 Sep 2021

Cited by 2 | Viewed by 1899

Abstract

Cholinesterases (ChEs) show increased activities in patients with Alzheimer’s disease, and remain one of the main therapeutic targets for treatment of this neurodegenerative disorder. A library of organoruthenium(II) complexes was prepared to investigate the influence of their structural elements on inhibition of ChEs, [...] Read more.

Cholinesterases (ChEs) show increased activities in patients with Alzheimer’s disease, and remain one of the main therapeutic targets for treatment of this neurodegenerative disorder. A library of organoruthenium(II) complexes was prepared to investigate the influence of their structural elements on inhibition of ChEs, and on another pharmacologically important group of enzymes, glutathione S-transferases (GSTs). Two groups of organoruthenium(II) compounds were considered: (i) organoruthenium(II) complexes with p-cymene as an arene ligand, and (ii) organoruthenium(II) carbonyl complexes as CO-releasing molecules. Eight organoruthenium complexes were screened for inhibitory activities against ChEs and GSTs of human and animal origins. Some compounds inhibited all of these enzymes at low micromolar concentrations, while others selectively inhibited either ChEs or GSTs. This study demonstrates the importance of the different structural elements of organoruthenium complexes for their inhibitory activities against ChEs and GSTs, and also proposes some interesting compounds for further preclinical testing as ChE or GST inhibitory drugs. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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18 pages, 6127 KiB

Open AccessArticle

Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer’s Disease

by Ekaterina A. Rudnitskaya, Tatiana A. Kozlova, Alena O. Burnyasheva, Natalia A. Stefanova and Nataliya G. Kolosova

Biomedicines 2021, 9(7), 823; https://doi.org/10.3390/biomedicines9070823 - 15 Jul 2021

Cited by 8 | Viewed by 2283

Abstract

Sporadic Alzheimer’s disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis [...] Read more.

Sporadic Alzheimer’s disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis of “neurodevelopmental origin of neurodegenerative disorders”: prerequisites for neurodegeneration may occur during early brain development. Therefore, we investigated the development of the most AD-affected brain structures (hippocampus and prefrontal cortex) using an immunohistochemical approach in senescence-accelerated OXYS rats, which are considered a suitable model of the most common—sporadic—type of AD. We noticed an additional peak of neurogenesis, which coincides in time with the peak of apoptosis in the hippocampus of OXYS rats on postnatal day three. Besides, we showed signs of delayed migration of neurons to the prefrontal cortex as well as disturbances in astrocytic and microglial support of the hippocampus and prefrontal cortex during the first postnatal week. Altogether, our results point to dysmaturation during early development of the brain—especially insufficient glial support—as a possible “first hit” leading to neurodegenerative processes and AD pathology manifestation later in life. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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22 pages, 4045 KiB

Open AccessArticle

Evidence of Neurovascular Un-Coupling in Mild Alzheimer’s Disease through Multimodal EEG-fNIRS and Multivariate Analysis of Resting-State Data

by Antonio M. Chiarelli, David Perpetuini, Pierpaolo Croce, Chiara Filippini, Daniela Cardone, Ludovica Rotunno, Nelson Anzoletti, Michele Zito, Filippo Zappasodi and Arcangelo Merla

Biomedicines 2021, 9(4), 337; https://doi.org/10.3390/biomedicines9040337 - 26 Mar 2021

Cited by 21 | Viewed by 3330

Abstract

Alzheimer’s disease (AD) is associated with modifications in cerebral blood perfusion and autoregulation. Hence, neurovascular coupling (NC) alteration could become a biomarker of the disease. NC might be assessed in clinical settings through multimodal electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). Multimodal EEG-fNIRS [...] Read more.

Alzheimer’s disease (AD) is associated with modifications in cerebral blood perfusion and autoregulation. Hence, neurovascular coupling (NC) alteration could become a biomarker of the disease. NC might be assessed in clinical settings through multimodal electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). Multimodal EEG-fNIRS was recorded at rest in an ambulatory setting to assess NC and to evaluate the sensitivity and specificity of the methodology to AD. Global NC was evaluated with a general linear model (GLM) framework by regressing whole-head EEG power envelopes in three frequency bands (theta, alpha and beta) with average fNIRS oxy- and deoxy-hemoglobin concentration changes in the frontal and prefrontal cortices. NC was lower in AD compared to healthy controls (HC) with significant differences in the linkage of theta and alpha bands with oxy- and deoxy-hemoglobin, respectively (p = 0.028 and p = 0.020). Importantly, standalone EEG and fNIRS metrics did not highlight differences between AD and HC. Furthermore, a multivariate data-driven analysis of NC between the three frequency bands and the two hemoglobin species delivered a cross-validated classification performance of AD and HC with an Area Under the Curve, AUC = 0.905 (p = 2.17 × 10⁻⁵). The findings demonstrate that EEG-fNIRS may indeed represent a powerful ecological tool for clinical evaluation of NC and early identification of AD. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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Review

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13 pages, 690 KiB

Open AccessReview

Microglia and Cholesterol Handling: Implications for Alzheimer’s Disease

by Oscar M. Muñoz Herrera and Angela M. Zivkovic

Biomedicines 2022, 10(12), 3105; https://doi.org/10.3390/biomedicines10123105 - 01 Dec 2022

Cited by 8 | Viewed by 2815

Abstract

Cholesterol is essential for brain function and structure, however altered cholesterol metabolism and transport are hallmarks of multiple neurodegenerative conditions, including Alzheimer’s disease (AD). The well-established link between apolipoprotein E (APOE) genotype and increased AD risk highlights the importance of cholesterol and lipid [...] Read more.

Cholesterol is essential for brain function and structure, however altered cholesterol metabolism and transport are hallmarks of multiple neurodegenerative conditions, including Alzheimer’s disease (AD). The well-established link between apolipoprotein E (APOE) genotype and increased AD risk highlights the importance of cholesterol and lipid transport in AD etiology. Whereas more is known about the regulation and dysregulation of cholesterol metabolism and transport in neurons and astrocytes, less is known about how microglia, the immune cells of the brain, handle cholesterol, and the subsequent implications for the ability of microglia to perform their essential functions. Evidence is emerging that a high-cholesterol environment, particularly in the context of defects in the ability to transport cholesterol (e.g., expression of the high-risk APOE4 isoform), can lead to chronic activation, increased inflammatory signaling, and reduced phagocytic capacity, which have been associated with AD pathology. In this narrative review we describe how cholesterol regulates microglia phenotype and function, and discuss what is known about the effects of statins on microglia, as well as highlighting areas of future research to advance knowledge that can lead to the development of novel therapies for the prevention and treatment of AD. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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18 pages, 838 KiB

Open AccessReview

Modifiable Innate Biology within the Gut–Brain Axis for Alzheimer’s Disease

by Helena Marcos Pasero, Aurora García Tejedor, Juan Antonio Giménez-Bastida and José Moisés Laparra Llopis

Biomedicines 2022, 10(9), 2098; https://doi.org/10.3390/biomedicines10092098 - 27 Aug 2022

Cited by 1 | Viewed by 2739

Abstract

Alzheimer’s disease (AD) is a prototypical inflammation-associated loss of cognitive function, with approximately 90% of the AD burden associated with invading myeloid cells controlling the function of the resident microglia. This indicates that the immune microenvironment has a pivotal role in the pathogenesis [...] Read more.

Alzheimer’s disease (AD) is a prototypical inflammation-associated loss of cognitive function, with approximately 90% of the AD burden associated with invading myeloid cells controlling the function of the resident microglia. This indicates that the immune microenvironment has a pivotal role in the pathogenesis of the disease. Multiple peripheral stimuli, conditioned by complex and varied interactions between signals that stem at the intestinal level and neuroimmune processes, are involved in the progression and severity of AD. Conceivably, the targeting of critical innate immune signals and cells is achievable, influencing immune and metabolic health within the gut–brain axis. Considerable progress has been made, modulating many different metabolic and immune alterations that can drive AD development. However, non-pharmacological strategies targeting immunometabolic processes affecting neuroinflammation in AD treatment remain general and, at this point, are applied to all patients regardless of disease features. Despite these possibilities, improved knowledge of the relative contribution of the different innate immune cells and molecules comprising the chronically inflamed brain network to AD pathogenesis, and elucidation of the network hierarchy, are needed for planning potent preventive and/or therapeutic interventions. Moreover, an integrative perspective addressing transdisciplinary fields can significantly contribute to molecular pathological epidemiology, improving the health and quality of life of AD patients. This review is intended to gather modifiable immunometabolic processes based on their importance in the prevention and management of AD. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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13 pages, 977 KiB

Open AccessReview

Diverse Roles of Ceramide in the Progression and Pathogenesis of Alzheimer’s Disease

by Md Riad Chowdhury, Hee Kyung Jin and Jae-sung Bae

Biomedicines 2022, 10(8), 1956; https://doi.org/10.3390/biomedicines10081956 - 12 Aug 2022

Cited by 14 | Viewed by 2509

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and is associated with several pathophysiological features, including cellular dysfunction, failure of neurotransmission, cognitive impairment, cell death, and other clinical consequences. Advanced research on the pathogenesis of AD has elucidated a mechanistic framework and [...] Read more.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and is associated with several pathophysiological features, including cellular dysfunction, failure of neurotransmission, cognitive impairment, cell death, and other clinical consequences. Advanced research on the pathogenesis of AD has elucidated a mechanistic framework and revealed many therapeutic possibilities. Among the mechanisms, sphingolipids are mentioned as distinctive mediators to be associated with the pathology of AD. Reportedly, alteration in the metabolism of sphingolipids and their metabolites result in the dysfunction of mitochondria, autophagy, amyloid beta regulation, and neuronal homeostasis, which exacerbates AD progression. Considering the importance of sphingolipids, in this review, we discuss the role of ceramide, a bioactive sphingolipid metabolite, in the progression and pathogenesis of AD. Herein, we describe the ceramide synthesis pathway and its involvement in the dysregulation of homeostasis, which eventually leads to AD. Furthermore, this review references different therapeutics proposed to modulate the ceramide pathway to maintain ceramide levels and prevent the disease progression. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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34 pages, 1055 KiB

Open AccessReview

Direct Oral Anticoagulants (DOACs) for Therapeutic Targeting of Thrombin, a Key Mediator of Cerebrovascular and Neuronal Dysfunction in Alzheimer’s Disease

by Klaus Grossmann

Biomedicines 2022, 10(8), 1890; https://doi.org/10.3390/biomedicines10081890 - 04 Aug 2022

Cited by 9 | Viewed by 3437

Abstract

Although preclinical research and observer studies on patients with atrial fibrillation concluded that direct oral anticoagulants (DOACs) can protect against dementia like Alzheimer’s disease (AD), clinical investigation towards therapeutical approval is still pending. DOACs target pathological thrombin, which is, like toxic tau and [...] Read more.

Although preclinical research and observer studies on patients with atrial fibrillation concluded that direct oral anticoagulants (DOACs) can protect against dementia like Alzheimer’s disease (AD), clinical investigation towards therapeutical approval is still pending. DOACs target pathological thrombin, which is, like toxic tau and amyloid-ß proteins (Aß), an early hallmark of AD. Especially in hippocampal and neocortical areas, the release of parenchymal Aß into the blood induces thrombin and proinflammatory bradykinin synthesis by activating factor XII of the contact system. Thrombin promotes platelet aggregation and catalyzes conversion of fibrinogen to fibrin, leading to degradation-resistant, Aß-containing fibrin clots. Together with oligomeric Aß, these clots trigger vessel constriction and cerebral amyloid angiopathy (CAA) with vessel occlusion and hemorrhages, leading to vascular and blood–brain barrier (BBB) dysfunction. As consequences, brain blood flow, perfusion, and supply with oxygen (hypoxia) and nutrients decrease. In parenchymal tissue, hypoxia stimulates Aß synthesis, leading to Aß accumulation, which is further enhanced by BBB-impaired perivascular Aß clearance. Aß trigger neuronal damage and promote tau pathologies. BBB dysfunction enables thrombin and fibrin(ogen) to migrate into parenchymal tissue and to activate glial cells. Inflammation and continued Aß production are the results. Synapses and neurons die, and cognitive abilities are lost. DOACs block thrombin by inhibiting its activity (dabigatran) or production (FXa-inhibitors, e.g., apixaban, rivaroxaban). Therefore, DOAC use could preserve vascular integrity and brain perfusion and, thereby, could counteract vascular-driven neuronal and cognitive decline in AD. A conception for clinical investigation is presented, focused on DOAC treatment of patients with diagnosed AD in early-stage and low risk of major bleeding. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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19 pages, 1255 KiB

Open AccessEditor’s ChoiceReview

Development of Alzheimer’s Disease Biomarkers: From CSF- to Blood-Based Biomarkers

by Sakulrat Mankhong, Sujin Kim, Seongju Lee, Hyo-Bum Kwak, Dong-Ho Park, Kyung-Lim Joa and Ju-Hee Kang

Biomedicines 2022, 10(4), 850; https://doi.org/10.3390/biomedicines10040850 - 05 Apr 2022

Cited by 19 | Viewed by 11362

Abstract

In the 115 years since the discovery of Alzheimer’s disease (AD), our knowledge, diagnosis, and therapeutics have significantly improved. Biomarkers are the primary tools for clinical research, diagnostics, and therapeutic monitoring in clinical trials. They provide much insightful information, and while they are [...] Read more.

In the 115 years since the discovery of Alzheimer’s disease (AD), our knowledge, diagnosis, and therapeutics have significantly improved. Biomarkers are the primary tools for clinical research, diagnostics, and therapeutic monitoring in clinical trials. They provide much insightful information, and while they are not clinically used routinely, they help us to understand the mechanisms of this disease. This review charts the journey of AD biomarker discovery and development from cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (p-tau) biomarkers and imaging technologies to the next generation of biomarkers. We also discuss advanced high-sensitivity assay platforms for CSF Aβ42, T-tau, p-tau, and blood analysis. The recently proposed Aβ deposition/tau biomarker/neurodegeneration or neuronal injury (ATN) scheme might facilitate the definition of the biological status underpinning AD and offer a common language among researchers across biochemical biomarkers and imaging. Moreover, we highlight blood-based biomarkers for AD that offer a scalable alternative to CSF biomarkers through cost-saving and reduced invasiveness, and may provide an understanding of disease initiation and development. We discuss different groups of blood-based biomarker candidates, their advantages and limitations, and paths forward, from identification and analysis to clinical validation. The development of valid blood-based biomarkers may facilitate the implementation of future AD therapeutics and diagnostics. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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19 pages, 1569 KiB

Open AccessReview

The Road to Personalized Medicine in Alzheimer’s Disease: The Use of Artificial Intelligence

by Anuschka Silva-Spínola, Inês Baldeiras, Joel P. Arrais and Isabel Santana

Biomedicines 2022, 10(2), 315; https://doi.org/10.3390/biomedicines10020315 - 29 Jan 2022

Cited by 14 | Viewed by 6119

Abstract

Dementia remains an extremely prevalent syndrome among older people and represents a major cause of disability and dependency. Alzheimer’s disease (AD) accounts for the majority of dementia cases and stands as the most common neurodegenerative disease. Since age is the major risk factor [...] Read more.

Dementia remains an extremely prevalent syndrome among older people and represents a major cause of disability and dependency. Alzheimer’s disease (AD) accounts for the majority of dementia cases and stands as the most common neurodegenerative disease. Since age is the major risk factor for AD, the increase in lifespan not only represents a rise in the prevalence but also adds complexity to the diagnosis. Moreover, the lack of disease-modifying therapies highlights another constraint. A shift from a curative to a preventive approach is imminent and we are moving towards the application of personalized medicine where we can shape the best clinical intervention for an individual patient at a given point. This new step in medicine requires the most recent tools and analysis of enormous amounts of data where the application of artificial intelligence (AI) plays a critical role on the depiction of disease–patient dynamics, crucial in reaching early/optimal diagnosis, monitoring and intervention. Predictive models and algorithms are the key elements in this innovative field. In this review, we present an overview of relevant topics regarding the application of AI in AD, detailing the algorithms and their applications in the fields of drug discovery, and biomarkers. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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35 pages, 1860 KiB

Open AccessReview

Neuroimaging of Mouse Models of Alzheimer’s Disease

by Amandine Jullienne, Michelle V. Trinh and Andre Obenaus

Biomedicines 2022, 10(2), 305; https://doi.org/10.3390/biomedicines10020305 - 28 Jan 2022

Cited by 12 | Viewed by 4601

Abstract

Magnetic resonance imaging (MRI) and positron emission tomography (PET) have made great strides in the diagnosis and our understanding of Alzheimer’s Disease (AD). Despite the knowledge gained from human studies, mouse models have and continue to play an important role in deciphering the [...] Read more.

Magnetic resonance imaging (MRI) and positron emission tomography (PET) have made great strides in the diagnosis and our understanding of Alzheimer’s Disease (AD). Despite the knowledge gained from human studies, mouse models have and continue to play an important role in deciphering the cellular and molecular evolution of AD. MRI and PET are now being increasingly used to investigate neuroimaging features in mouse models and provide the basis for rapid translation to the clinical setting. Here, we provide an overview of the human MRI and PET imaging landscape as a prelude to an in-depth review of preclinical imaging in mice. A broad range of mouse models recapitulate certain aspects of the human AD, but no single model simulates the human disease spectrum. We focused on the two of the most popular mouse models, the 3xTg-AD and the 5xFAD models, and we summarized all known published MRI and PET imaging data, including contrasting findings. The goal of this review is to provide the reader with broad framework to guide future studies in existing and future mouse models of AD. We also highlight aspects of MRI and PET imaging that could be improved to increase rigor and reproducibility in future imaging studies. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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27 pages, 443 KiB

Open AccessReview

Modeling Alzheimer’s Disease in Caenorhabditis elegans

by Javier Alvarez, Pilar Alvarez-Illera, Jaime Santo-Domingo, Rosalba I. Fonteriz and Mayte Montero

Biomedicines 2022, 10(2), 288; https://doi.org/10.3390/biomedicines10020288 - 26 Jan 2022

Cited by 19 | Viewed by 7340

Abstract

Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease [...] Read more.

Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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14 pages, 1525 KiB

Open AccessReview

Choroid Plexus in Alzheimer’s Disease—The Current State of Knowledge

by Tiago Gião, Tiago Teixeira, Maria Rosário Almeida and Isabel Cardoso

Biomedicines 2022, 10(2), 224; https://doi.org/10.3390/biomedicines10020224 - 21 Jan 2022

Cited by 21 | Viewed by 5550

Abstract

The choroid plexus (CP), located in each of the four ventricles of the brain, is formed by a monolayer of epithelial cells that surrounds a highly vascularized connective tissue with permeable capillaries. These cells are joined by tight junctions forming the blood–cerebrospinal fluid [...] Read more.

The choroid plexus (CP), located in each of the four ventricles of the brain, is formed by a monolayer of epithelial cells that surrounds a highly vascularized connective tissue with permeable capillaries. These cells are joined by tight junctions forming the blood–cerebrospinal fluid barrier (BCSFB), which strictly regulates the exchange of substances between the blood and cerebrospinal fluid (CSF). The primary purpose of the CP is to secrete CSF, but it also plays a role in the immune surveillance of the central nervous system (CNS) and in the removal of neurotoxic compounds from the CSF. According to recent findings, the CP is also involved in the modulation of the circadian cycle and neurogenesis. In diseases such as Alzheimer’s disease (AD), the function of the CP is impaired, resulting in an altered secretory, barrier, transport, and immune function. This review describes the current state of knowledge concerning the roles of the CP and BCSFB in the pathophysiology of AD and summarizes recently proposed therapies that aim to restore CP and BCSFB functions. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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16 pages, 2050 KiB

Open AccessReview

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer’s Disease

by Victoria García-Morales, Anabel González-Acedo, Lucía Melguizo-Rodríguez, Teresa Pardo-Moreno, Víctor Javier Costela-Ruiz, María Montiel-Troya and Juan José Ramos-Rodríguez

Biomedicines 2021, 9(12), 1910; https://doi.org/10.3390/biomedicines9121910 - 14 Dec 2021

Cited by 34 | Viewed by 6553

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by cognitive decline and progressive memory loss. The aim of this review was to update the state of knowledge on the pathophysiological mechanisms, diagnostic methods and therapeutic approach to AD. [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by cognitive decline and progressive memory loss. The aim of this review was to update the state of knowledge on the pathophysiological mechanisms, diagnostic methods and therapeutic approach to AD. Currently, the amyloid cascade hypothesis remains the leading theory in the pathophysiology of AD. This hypothesis states that amyloid-β (Aβ) deposition triggers a chemical cascade of events leading to the development of AD dementia. The antemortem diagnosis of AD is still based on clinical parameters. Diagnostic procedures in AD include fluid-based biomarkers such as those present in cerebrospinal fluid and plasma or diagnostic imaging methods. Currently, the therapeutic armory available focuses on symptom control and is based on four pillars: pharmacological treatment where acetylcholinesterase inhibitors stand out; pharmacological treatment under investigation which includes drugs focused on the control of Aβ pathology and tau hyperphosphorylation; treatment focusing on risk factors such as diabetes; or nonpharmacological treatments aimed at preventing development of the disease or treating symptoms through occupational therapy or psychological help. AD remains a largely unknown disease. Further research is needed to identify new biomarkers and therapies that can prevent progression of the pathology. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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13 pages, 3297 KiB

Open AccessReview

A Perspective on the Development of c-Jun N-terminal Kinase Inhibitors as Therapeutics for Alzheimer’s Disease: Investigating Structure through Docking Studies

by Hyunwook Cho and Jung-Mi Hah

Biomedicines 2021, 9(10), 1431; https://doi.org/10.3390/biomedicines9101431 - 09 Oct 2021

Cited by 10 | Viewed by 2054

Abstract

c-Jun N-terminal kinase (JNK) plays an important role in cell death caused by various stimuli. Because the isoform JNK3 is mainly expressed in the brain, it is believed to play a pivotal role in various neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s [...] Read more.

c-Jun N-terminal kinase (JNK) plays an important role in cell death caused by various stimuli. Because the isoform JNK3 is mainly expressed in the brain, it is believed to play a pivotal role in various neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), which still lack plausible therapeutics. To develop a novel and selective JNK3 inhibitor, we conducted a decadal review (2011 to 2021) of published articles on JNK inhibitors, particularly those focusing on a structural perspective and docking insights. We observed the structures of three isoforms of JNK, namely holo-proteins and co-crystal structures, with JNK3 inhibitors and summarized the significant structural aspects of selective JNK3 inhibitors as AD therapeutics. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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38 pages, 10499 KiB

Open AccessSystematic Review

A Systematic Review and Meta-Analysis of Cerebrospinal Fluid Amyloid and Tau Levels Identifies Mild Cognitive Impairment Patients Progressing to Alzheimer’s Disease

by Yunxing Ma, Julia Brettschneider and Joanna F. Collingwood

Biomedicines 2022, 10(7), 1713; https://doi.org/10.3390/biomedicines10071713 - 15 Jul 2022

Cited by 6 | Viewed by 2273

Abstract

Reported levels of amyloid-beta and tau in human cerebrospinal fluid (CSF) were evaluated to discover if these biochemical markers can predict the transition from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD). A systematic review of the literature in PubMed and Web of [...] Read more.

Reported levels of amyloid-beta and tau in human cerebrospinal fluid (CSF) were evaluated to discover if these biochemical markers can predict the transition from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD). A systematic review of the literature in PubMed and Web of Science (April 2021) was performed by a single researcher to identify studies reporting immunologically-based (xMAP or ELISA) measures of CSF analytes Aβ(1-42) and/or P-tau and/or T-tau in clinical studies with at least two timepoints and a statement of diagnostic criteria. Of 1137 screened publications, 22 met the inclusion criteria for CSF Aβ(1-42) measures, 20 studies included T-tau, and 17 included P-tau. Six meta-analyses were conducted to compare the analytes for healthy controls (HC) versus progressive MCI (MCI_AD) and for non-progressive MCI (Stable_MCI) versus MCI_AD; effect sizes were determined using random effects models. The heterogeneity of effect sizes across studies was confirmed with very high significance (p < 0.0001) for all meta-analyses except HC versus MCI_AD T-tau (p < 0.05) and P-tau (non-significant). Standard mean difference (SMD) was highly significant (p < 0.0001) for all comparisons (Stable_MCI versus MCI_AD: SMD [95%-CI] Aβ(1-42) = 1.19 [0.96,1.42]; T-tau = −1.03 [−1.24,−0.82]; P-tau = −1.03 [−1.47,−0.59]; HC versus MCI_AD: SMD Aβ(1-42) = 1.73 [1.39,2.07]; T-tau = −1.13 [−1.33,−0.93]; P-tau = −1.10 [−1.23,−0.96]). The follow-up interval in longitudinal evaluations was a critical factor in clinical study design, and the Aβ(1–42)/P-tau ratio most robustly differentiated progressive from non-progressive MCI. The value of amyloid-beta and tau as markers of patient outcome are supported by these findings. Full article

(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)

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