Cells

2024

Jump to: 2023, 2022

32 pages, 1448 KiB

Open AccessReview

Therapeutic Targets in Innate Immunity to Tackle Alzheimer’s Disease

by Maria L. Serradas, Yingying Ding, Paula V. Martorell, Ida Kulińska and Sergio Castro-Gomez

Cells 2024, 13(17), 1426; https://doi.org/10.3390/cells13171426 - 26 Aug 2024

Viewed by 2860

Abstract

There is an urgent need for effective disease-modifying therapeutic interventions for Alzheimer’s disease (AD)—the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks of this disease—β-amyloid plaques and neurofibrillary tangles—failed, showed discrete clinical effects, or [...] Read more.

There is an urgent need for effective disease-modifying therapeutic interventions for Alzheimer’s disease (AD)—the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks of this disease—β-amyloid plaques and neurofibrillary tangles—failed, showed discrete clinical effects, or were accompanied by concerning side effects. There has been an ongoing search for novel therapeutic targets. Neuroinflammation, now widely recognized as a hallmark of all neurodegenerative diseases, has been proven to be a major contributor to AD pathology. Here, we summarize the role of neuroinflammation in the pathogenesis and progression of AD and discuss potential targets such as microglia, TREM2, the complement system, inflammasomes, and cytosolic DNA sensors. We also present an overview of ongoing studies targeting specific innate immune system components, highlighting the progress in this field of drug research while bringing attention to the delicate nature of innate immune modulations in AD. Full article

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21 pages, 1980 KiB

Open AccessReview

Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?

by Francesco Agostini, Bibiana Sgalletta and Marco Bisaglia

Cells 2024, 13(16), 1376; https://doi.org/10.3390/cells13161376 - 19 Aug 2024

Cited by 1 | Viewed by 999

Abstract

Iron is an essential metal ion implicated in several cellular processes. However, the reactive nature of iron renders this metal ion potentially dangerous for cells, and its levels need to be tightly controlled. Alterations in the intracellular concentration of iron are associated with [...] Read more.

Iron is an essential metal ion implicated in several cellular processes. However, the reactive nature of iron renders this metal ion potentially dangerous for cells, and its levels need to be tightly controlled. Alterations in the intracellular concentration of iron are associated with different neuropathological conditions, including neurodegeneration with brain iron accumulation (NBIA). As the name suggests, NBIA encompasses a class of rare and still poorly investigated neurodegenerative disorders characterized by an abnormal accumulation of iron in the brain. NBIA is mostly a genetic pathology, and to date, 10 genes have been linked to familial forms of NBIA. In the present review, after the description of the principal mechanisms implicated in iron homeostasis, we summarize the research data concerning the pathological mechanisms underlying the genetic forms of NBIA and discuss the potential involvement of iron in such processes. The picture that emerges is that, while iron overload can contribute to the pathogenesis of NBIA, it does not seem to be the causal factor in most forms of the pathology. The onset of these pathologies is rather caused by a combination of processes involving the interplay between lipid metabolism, mitochondrial functions, and autophagic activity, eventually leading to iron dyshomeostasis. Full article

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19 pages, 1356 KiB

Open AccessReview

circRNAs as Epigenetic Regulators of Integrity in Blood–Brain Barrier Architecture: Mechanisms and Therapeutic Strategies in Multiple Sclerosis

by Elisabetta D’Aversa, Francesca Salvatori, Mauro Vaccarezza, Bianca Antonica, Miriana Grisafi, Ajay Vikram Singh, Paola Secchiero, Giorgio Zauli, Veronica Tisato and Donato Gemmati

Cells 2024, 13(16), 1316; https://doi.org/10.3390/cells13161316 - 6 Aug 2024

Viewed by 1311

Abstract

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease leading to progressive demyelination and neuronal loss, with extensive neurological symptoms. As one of the most widespread neurodegenerative disorders, with an age onset of about 30 years, it turns out to be a socio-health [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease leading to progressive demyelination and neuronal loss, with extensive neurological symptoms. As one of the most widespread neurodegenerative disorders, with an age onset of about 30 years, it turns out to be a socio-health and economic issue, thus necessitating therapeutic interventions currently unavailable. Loss of integrity in the blood–brain barrier (BBB) is one of the distinct MS hallmarks. Brain homeostasis is ensured by an endothelial cell-based monolayer at the interface between the central nervous system (CNS) and systemic bloodstream, acting as a selective barrier. MS results in enhanced barrier permeability, mainly due to the breakdown of tight (TJs) and adherens junctions (AJs) between endothelial cells. Specifically, proinflammatory mediator release causes failure in cytoplasmic exposure of junctions, resulting in compromised BBB integrity that enables blood cells to cross the barrier, establishing iron deposition and neuronal impairment. Cells with a compromised cytoskeletal protein network, fiber reorganization, and discontinuous junction structure can occur, resulting in BBB dysfunction. Recent investigations on spatial transcriptomics have proven circularRNAs (circRNAs) to be powerful multi-functional molecules able to epigenetically regulate transcription and structurally support proteins. In the present review, we provide an overview of the recent role ascribed to circRNAs in maintaining BBB integrity/permeability via cytoskeletal stability. Increased knowledge of the mechanisms responsible for impairment and circRNA’s role in driving BBB damage and dysfunction might be helpful for the recognition of novel therapeutic targets to overcome BBB damage and unrestrained neurodegeneration. Full article

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29 pages, 1309 KiB

Open AccessReview

Alpha Synuclein Toxicity and Non-Motor Parkinson’s

by Gabriella M. Mazzotta and Carmela Conte

Cells 2024, 13(15), 1265; https://doi.org/10.3390/cells13151265 - 27 Jul 2024

Viewed by 1680

Abstract

Parkinson’s disease (PD) is a common multisystem neurodegenerative disorder affecting 1% of the population over the age of 60 years. The main neuropathological features of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of [...] Read more.

Parkinson’s disease (PD) is a common multisystem neurodegenerative disorder affecting 1% of the population over the age of 60 years. The main neuropathological features of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of alpha synuclein (αSyn)-rich Lewy bodies both manifesting with classical motor signs. αSyn has emerged as a key protein in PD pathology as it can spread through synaptic networks to reach several anatomical regions of the body contributing to the appearance of non-motor symptoms (NMS) considered prevalent among individuals prior to PD diagnosis and persisting throughout the patient’s life. NMS mainly includes loss of taste and smell, constipation, psychiatric disorders, dementia, impaired rapid eye movement (REM) sleep, urogenital dysfunction, and cardiovascular impairment. This review summarizes the more recent findings on the impact of αSyn deposits on several prodromal NMS and emphasizes the importance of early detection of αSyn toxic species in biofluids and peripheral biopsies as prospective biomarkers in PD. Full article

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30 pages, 840 KiB

Open AccessReview

Unraveling the Potential Underlying Mechanisms of Mild Behavioral Impairment: Focusing on Amyloid and Tau Pathology

by Efthalia Angelopoulou, Anastasia Bougea, Alexandros Hatzimanolis, Nikolaos Scarmeas and Sokratis G. Papageorgiou

Cells 2024, 13(13), 1164; https://doi.org/10.3390/cells13131164 - 8 Jul 2024

Viewed by 1736

Abstract

The emergence of sustained neuropsychiatric symptoms (NPS) among non-demented individuals in later life, defined as mild behavioral impairment (MBI), is linked to a higher risk of cognitive decline. However, the underlying pathophysiological mechanisms remain largely unexplored. A growing body of evidence has shown [...] Read more.

The emergence of sustained neuropsychiatric symptoms (NPS) among non-demented individuals in later life, defined as mild behavioral impairment (MBI), is linked to a higher risk of cognitive decline. However, the underlying pathophysiological mechanisms remain largely unexplored. A growing body of evidence has shown that MBI is associated with alterations in structural and functional neuroimaging studies, higher genetic predisposition to clinical diagnosis of Alzheimer’s disease (AD), as well as amyloid and tau pathology assessed in the blood, cerebrospinal fluid, positron-emission tomography (PET) imaging and neuropathological examination. These findings shed more light on the MBI-related potential neurobiological mechanisms, paving the way for the development of targeted pharmacological approaches. In this review, we aim to discuss the available clinical evidence on the role of amyloid and tau pathology in MBI and the potential underlying pathophysiological mechanisms. Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, disruption of neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), abnormal neuroinflammatory responses including the kynurenine pathway, dysregulation of transforming growth factor beta (TGF-β1), epigenetic alterations including micro-RNA (miR)-451a and miR-455-3p, synaptic dysfunction, imbalance in neurotransmitters including acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA) and norepinephrine, as well as altered locus coeruleus (LC) integrity are some of the potential mechanisms connecting MBI with amyloid and tau pathology. The elucidation of the underlying neurobiology of MBI would facilitate the design and efficacy of relative clinical trials, especially towards amyloid- or tau-related pathways. In addition, we provide insights for future research into our deeper understanding of its underlying pathophysiology of MBI, and discuss relative therapeutic implications. Full article

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21 pages, 2966 KiB

Open AccessArticle

Elevated NLRP3 Inflammasome Activation Is Associated with Motor Neuron Degeneration in ALS

by Hilal Cihankaya, Verian Bader, Konstanze F. Winklhofer, Matthias Vorgerd, Johann Matschke, Sarah Stahlke, Carsten Theiss and Veronika Matschke

Cells 2024, 13(12), 995; https://doi.org/10.3390/cells13120995 - 7 Jun 2024

Cited by 1 | Viewed by 1497

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the central nervous system. Recent research has increasingly linked the activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome to ALS pathogenesis. NLRP3 activation triggers Caspase 1 [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the central nervous system. Recent research has increasingly linked the activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome to ALS pathogenesis. NLRP3 activation triggers Caspase 1 (CASP 1) auto-activation, leading to the cleavage of Gasdermin D (GSDMD) and pore formation on the cellular membrane. This process facilitates cytokine secretion and ultimately results in pyroptotic cell death, highlighting the complex interplay of inflammation and neurodegeneration in ALS. This study aimed to characterize the NLRP3 inflammasome components and their colocalization with cellular markers using the wobbler mouse as an ALS animal model. Firstly, we checked the levels of miR-223-3p because of its association with NLRP3 inflammasome activity. The wobbler mice showed an increased expression of miR-223-3p in the ventral horn, spinal cord, and cerebellum tissues. Next, increased levels of NLRP3, pro-CASP 1, cleaved CASP 1 (c-CASP 1), full-length GSDMD, and cleaved GDSMD revealed NLRP3 inflammasome activation in wobbler spinal cords, but not in the cerebellum. Furthermore, we investigated the colocalization of the aforementioned proteins with neurons, microglia, and astrocyte markers in the spinal cord tissue. Evidently, the wobbler mice displayed microgliosis, astrogliosis, and motor neuron degeneration in this tissue. Additionally, we showed the upregulation of protein levels and the colocalization of NLRP3, c-CASP1, and GSDMD in neurons, as well as in microglia and astrocytes. Overall, this study demonstrated the involvement of NLRP3 inflammasome activation and pyroptotic cell death in the spinal cord tissue of wobbler mice, which could further exacerbate the motor neuron degeneration and neuroinflammation in this ALS mouse model. Full article

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14 pages, 1645 KiB

Open AccessArticle

Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy

by Paola Ruffo, Francesca De Amicis, Vincenzo La Bella and Francesca Luisa Conforti

Cells 2024, 13(8), 677; https://doi.org/10.3390/cells13080677 - 14 Apr 2024

Viewed by 1075

Abstract

The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences [...] Read more.

The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences in the human genome play a significant role in ALS pathophysiology. Investigating the frequency of repeat expansions in ALS in different populations and ethnic groups is therefore of great importance. Based on these premises, this study aimed to define the frequency of REs in the NIPA1, NOP56, and NOTCH2NLC genes and the possible associations between phenotypes and the size of REs in the Italian population. Using repeat-primed-PCR and PCR-fragment analyses, we screened 302 El-Escorial-diagnosed ALS patients and compared the RE distribution to 167 age-, gender-, and ethnicity-matched healthy controls. While the REs distribution was similar between the ALS and control groups, a moderate association was observed between longer RE lengths and clinical features such as age at onset, gender, site of onset, and family history. In conclusion, this is the first study to screen ALS patients from southern Italy for REs in NIPA1, NOP56, and NOTCH2NLC genes, contributing to our understanding of ALS genetics. Our results highlighted that the extremely rare pathogenic REs in these genes do not allow an association with the disease. Full article

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16 pages, 590 KiB

Open AccessOpinion

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

by Balázs Sonkodi

Cells 2024, 13(6), 492; https://doi.org/10.3390/cells13060492 - 12 Mar 2024

Cited by 2 | Viewed by 2533

Abstract

Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this is the theory that excessively prolonged proprioceptive mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading to Piezo2 channelopathy. This microinjury is suggested to provide one gateway from physiology to pathophysiology. The chronic, but not irreversible, form of this Piezo2 channelopathy is implicated in many diseases with unknown etiology. Dry eye disease is one of them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are proposed as the first critical link in this hierarchical ordered depletory pathomechanism as proton-collecting/distributing antennas; hence, they may play a role in ALS pathomechanism onset. Even more importantly, the shedding or charge-altering variants of Syndecan-3 may contribute to the Piezo2 channelopathy-induced disruption of the Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 and VGLUT2. Thus, these alterations may not only cause disruption to ultrafast signaling to the hippocampus in conscious proprioception, but could disrupt the ultrafast proprioceptive signaling feedback to the motoneurons. Correspondingly, an inert Piezo2-initiated proton-based ultrafast signaled proprioceptive skeletal system is coming to light that is suggested to be progressively lost in ALS. In addition, the lost functional link of the MyoD family of inhibitor proteins, as auxiliary subunits of Piezo2, may not only contribute to the theorized acquired Piezo2 channelopathy, but may explain how these microinjured ion channels evolve to be principal transcription activators. Full article

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16 pages, 786 KiB

Open AccessReview

Proximity-Induced Pharmacology for Amyloid-Related Diseases

by Andrea Bertran-Mostazo, Gabrielė Putriūtė, Irene Álvarez-Berbel, Maria Antònia Busquets, Carles Galdeano, Alba Espargaró and Raimon Sabate

Cells 2024, 13(5), 449; https://doi.org/10.3390/cells13050449 - 4 Mar 2024

Cited by 1 | Viewed by 2055

Abstract

Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer’s disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic [...] Read more.

Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer’s disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer’s disease. This level of specificity could allow for more targeted and effective treatments. With ongoing research and development, it is hoped that these treatments can be refined and optimized to provide even greater benefits to patients. As our understanding of the underlying mechanisms of these diseases continues to grow, proximity-induced pharmacology treatments may become an increasingly important tool in the fight against dementia and other related conditions. Full article

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16 pages, 1883 KiB

Open AccessPerspective

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

by Judit Oláh, Vic Norris, Attila Lehotzky and Judit Ovádi

Cells 2024, 13(4), 338; https://doi.org/10.3390/cells13040338 - 14 Feb 2024

Cited by 1 | Viewed by 1688

Abstract

Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin [...] Read more.

Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes. Full article

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2023

Jump to: 2024, 2022

17 pages, 4251 KiB

Open AccessArticle

Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport

by Svenja König, Nadine Schmidt, Karin Bechberger, Sarah Morris, Mercedes Priego, Hannah Zaky, Yuyu Song, Jan Pielage, Silke Brunholz, Scott T. Brady, Stefan Kins and Gerardo Morfini

Cells 2023, 12(19), 2403; https://doi.org/10.3390/cells12192403 - 4 Oct 2023

Viewed by 2354

Abstract

The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of [...] Read more.

The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of kinase signaling pathways is well established in the context of full-length APP, little is known about intracellular effects of the AICD fragment, particularly within discrete neuronal compartments. Deficits in fast axonal transport (FAT) and axonopathy documented in AD-affected neurons prompted us to evaluate potential axon-autonomous effects of the AICD fragment for the first time. Vesicle motility assays using the isolated squid axoplasm preparation revealed inhibition of FAT by AICD. Biochemical experiments linked this effect to aberrant activation of selected axonal kinases and heightened phosphorylation of the anterograde motor protein conventional kinesin, consistent with precedents showing phosphorylation-dependent regulation of motors proteins powering FAT. Pharmacological inhibitors of these kinases alleviated the AICD inhibitory effect on FAT. Deletion experiments indicated this effect requires a sequence encompassing the NPTY motif in AICD and interacting axonal proteins containing a phosphotyrosine-binding domain. Collectively, these results provide a proof of principle for axon-specific effects of AICD, further suggesting a potential mechanistic framework linking alterations in APP processing, FAT deficits, and axonal pathology in AD. Full article

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11 pages, 1661 KiB

Open AccessArticle

Basal Ganglia Compensatory White Matter Changes on DTI in Alzheimer’s Disease

by Zdeněk Wurst, Barbora Birčák Kuchtová, Jan Křemen, Anastasiya Lahutsina, Ibrahim Ibrahim, Jaroslav Tintěra, Aleš Bartoš, Marek Brabec, Tanya Rai, Petr Zach, Vladimír Musil, Nicoletta Olympiou and Jana Mrzílková

Cells 2023, 12(9), 1220; https://doi.org/10.3390/cells12091220 - 23 Apr 2023

Cited by 2 | Viewed by 2302

Abstract

The volume reduction of the gray matter structures in patients with Alzheimer’s disease is often accompanied by an asymmetric increase in the number of white matter fibers located close to these structures. The present study aims to investigate the white matter structure changes [...] Read more.

The volume reduction of the gray matter structures in patients with Alzheimer’s disease is often accompanied by an asymmetric increase in the number of white matter fibers located close to these structures. The present study aims to investigate the white matter structure changes in the motor basal ganglia in Alzheimer’s disease patients compared to healthy controls using diffusion tensor imaging. The amounts of tracts, tract length, tract volume, quantitative anisotropy, and general fractional anisotropy were measured in ten patients with Alzheimer’s disease and ten healthy controls. A significant decrease in the number of tracts and general fractional anisotropy was found in patients with Alzheimer’s disease compared to controls in the right caudate nucleus, while an increase was found in the left and the right putamen. Further, a significant decrease in the structural volume of the left and the right putamen was observed. An increase in the white matter diffusion tensor imaging parameters in patients with Alzheimer’s disease was observed only in the putamen bilaterally. The right caudate showed a decrease in both the diffusion tensor imaging parameters and the volume in Alzheimer’s disease patients. The right pallidum showed an increase in the diffusion tensor imaging parameters but a decrease in volume in Alzheimer’s disease patients. Full article

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2022

Jump to: 2024, 2023

25 pages, 2876 KiB

Open AccessReview

Pharmacotherapy Evolution in Alzheimer’s Disease: Current Framework and Relevant Directions

by Denisa Claudia Miculas, Paul Andrei Negru, Simona Gabriela Bungau, Tapan Behl, Syed Shams ul Hassan and Delia Mirela Tit

Cells 2023, 12(1), 131; https://doi.org/10.3390/cells12010131 - 28 Dec 2022

Cited by 34 | Viewed by 4602

Abstract

Alzheimer’s disease (AD), once considered a rare disease, is now the most common form of dementia in the elderly population. Current drugs (cholinesterase inhibitors and glutamate antagonists) are safe but of limited benefit to most patients, offering symptomatic relief without successful cure of [...] Read more.

Alzheimer’s disease (AD), once considered a rare disease, is now the most common form of dementia in the elderly population. Current drugs (cholinesterase inhibitors and glutamate antagonists) are safe but of limited benefit to most patients, offering symptomatic relief without successful cure of the disease. Since the last several decades, there has been a great need for the development of a treatment that might cure the underlying causes of AD and thereby slow its progression in vulnerable individuals. That is why phase I, II, and III studies that act on several fronts, such as cognitive improvement, symptom reduction, and enhancing the basic biology of AD, are imperative to stop the disease. This review discusses current treatment strategies, summarizing the clinical features and pharmacological properties, along with molecular docking analyses of the existing medications. Full article

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15 pages, 3128 KiB

Open AccessArticle

Fecal Microbiota Transplantation Reduces Pathology and Improves Cognition in a Mouse Model of Alzheimer’s Disease

by Shalini Elangovan, Thomas J. Borody and R. M. Damian Holsinger

Cells 2023, 12(1), 119; https://doi.org/10.3390/cells12010119 - 28 Dec 2022

Cited by 25 | Viewed by 4569

Abstract

Characterized by the presence of amyloid plaques, neurofibrillary tangles and neuroinflammation, Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no known treatment or cure. Global disease projections warrant an urgent and rapid therapeutic for the treatment of this devastating disease. Fecal microbiota [...] Read more.

Characterized by the presence of amyloid plaques, neurofibrillary tangles and neuroinflammation, Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no known treatment or cure. Global disease projections warrant an urgent and rapid therapeutic for the treatment of this devastating disease. Fecal microbiota transplantation (FMT) is a widely accepted and safely used treatment for recurrent Clostridium difficile infection and other metabolic diseases such as diabetes mellitus. FMT has also been demonstrated to be a possible AD therapeutic. We examined the potential of FMT for the treatment of AD in a robust, mouse model of the disease and report that a brief, 7-day treatment regimen demonstrated ‘plaque-busting’ and behavior-modifying effects in treated 5xFAD mice. Importantly, we show that donor age plays an important role in the efficacy of the treatment and these findings warrant further investigation in human trials. Full article

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2024

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