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17 pages, 44362 KiB

Open AccessEditor’s ChoiceArticle

Traumatic Brain Injury Leads to Alterations in Contusional Cortical miRNAs Involved in Dementia

by Shahmir Naseer, Laura Abelleira-Hervas, Dhwani Savani, Ross de Burgh, Robertas Aleksynas, Cornelius K. Donat, Nelofer Syed and Magdalena Sastre

Biomolecules 2022, 12(10), 1457; https://doi.org/10.3390/biom12101457 - 11 Oct 2022

Cited by 6 | Viewed by 2193

Abstract

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer’s disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains [...] Read more.

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer’s disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains of TBI patients; however, the mechanisms leading to AD neuropathology in TBI are still unknown. In this study, we hypothesized that focal TBI induces changes in miRNA expression in and around affected areas, resulting in the altered expression of genes involved in neurodegeneration and AD pathology. For this purpose, we performed a miRNA array in extracts from rats subjected to experimental TBI, using the controlled cortical impact (CCI) model. In and around the contusion, we observed alterations of miRNAs associated with dementia/AD, compared to the contralateral side. Specifically, the expression of miR-9 was significantly upregulated, while miR-29b, miR-34a, miR-106b, miR-181a and miR-107 were downregulated. Via qPCR, we confirmed these results in an additional group of injured rats when compared to naïve animals. Interestingly, the changes in those miRNAs were concomitant with alterations in the gene expression of mRNAs involved in amyloid generation and tau pathology, such as β-APP cleaving enzyme (BACE1) and Glycogen synthase-3-β (GSK3β). In addition increased levels of neuroinflammatory markers (TNF-α), glial activation, neuronal loss, and tau phosphorylation were observed in pericontusional areas. Therefore, our results suggest that the secondary injury cascade in TBI affects miRNAs regulating the expression of genes involved in AD dementia. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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18 pages, 2697 KiB

Open AccessEditor’s ChoiceArticle

Translocation of Distinct Alpha Synuclein Species from the Nucleus to Neuronal Processes during Neuronal Differentiation

by Katharina Pieger, Verena Schmitt, Carina Gauer, Nadja Gießl, Iryna Prots, Beate Winner, Jürgen Winkler, Johann Helmut Brandstätter and Wei Xiang

Biomolecules 2022, 12(8), 1108; https://doi.org/10.3390/biom12081108 - 12 Aug 2022

Cited by 3 | Viewed by 2035

Abstract

Alpha synuclein (aSyn) and its aggregation are crucial for the neurodegeneration of Parkinson’s disease (PD). aSyn was initially described in the nucleus and presynaptic nerve terminals. However, the biology of nuclear aSyn and the link of aSyn between subcellular compartments are less understood. [...] Read more.

Alpha synuclein (aSyn) and its aggregation are crucial for the neurodegeneration of Parkinson’s disease (PD). aSyn was initially described in the nucleus and presynaptic nerve terminals. However, the biology of nuclear aSyn and the link of aSyn between subcellular compartments are less understood. Current knowledge suggests the existence of various aSyn species with distinct structural and biochemical properties. Here, we identified a C-terminal-targeting aSyn antibody (Nu-aSyn-C), which has a high immunoaffinity towards aSyn in the nucleus. Comparing the Nu-aSyn-C antibody to aSyn antibodies developed against phosphorylated or aggregated forms, we observed that nuclear aSyn differs from cytosolic aSyn by an increased phosphorylation and assembly level in proliferating cells. Employing Nu-aSyn-C, we characterized aSyn distribution during neuronal differentiation in midbrain dopaminergic neurons (mDANs) derived from human-induced pluripotent stem cells (hiPSCs) and Lund human mesencephalic cells, and in primary rat hippocampal neurons. We detected a specific translocation pattern of aSyn during neuronal differentiation from the nucleus to the soma and finally to neuronal processes. Interestingly, a remarkable shift of Nu-aSyn-C-positive species towards neurites was detected in hiPSC mDANs from a PD patient carrying aSyn gene duplication. Together, our results reveal distinct nuclear and cytosolic aSyn species that redistribute during neuronal differentiation—a process that is altered in PD-derived neurons. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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17 pages, 27079 KiB

Open AccessArticle

Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model

by Alexandra Bluhm, Sarah Schrempel, Stephan Schilling, Stephan von Hörsten, Anja Schulze, Steffen Roßner and Maike Hartlage-Rübsamen

Biomolecules 2022, 12(7), 1006; https://doi.org/10.3390/biom12071006 - 20 Jul 2022

Cited by 2 | Viewed by 2326

Abstract

The deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but instead [...] Read more.

The deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but instead co-exist and interact with each other. Here, we investigated the presence of a newly identified, pyroglutamate79-modified α-synuclein variant (pGlu79-aSyn)—along with the enzyme matrix metalloproteinase-3 (MMP-3) and glutaminyl cyclase (QC) implicated in its formation—in AD and in the transgenic Tg2576 AD mouse model. In the human brain, pGlu79-aSyn was detected in cortical pyramidal neurons, with more distinct labeling in AD compared to control brain tissue. Using immunohistochemical double and triple labelings and confocal laser scanning microscopy, we demonstrate an association of pGlu79-aSyn, MMP-3 and QC with β-amyloid plaques. In addition, pGlu79-aSyn and QC were present in amyloid plaque-associated reactive astrocytes that were also immunoreactive for the chaperone heat shock protein 27 (HSP27). Our data are consistent for the transgenic mouse model and the human clinical condition. We conclude that pGlu79-aSyn can be generated extracellularly or within reactive astrocytes, accumulates in proximity to β-amyloid plaques and induces an astrocytic protein unfolding mechanism involving HSP27. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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16 pages, 7465 KiB

Open AccessEditor’s ChoiceArticle

Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses

by Praveen Bathini, Tao Sun, Mathias Schenk, Stephan Schilling, Nathan J. McDannold and Cynthia A. Lemere

Biomolecules 2022, 12(7), 951; https://doi.org/10.3390/biom12070951 - 06 Jul 2022

Cited by 8 | Viewed by 2690

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound [...] Read more.

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5–6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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22 pages, 19026 KiB

Open AccessArticle

Tau Protein Modulates Perineuronal Extracellular Matrix Expression in the TauP301L-acan Mouse Model

by Sophie Schmidt, Max Holzer, Thomas Arendt, Mandy Sonntag and Markus Morawski

Biomolecules 2022, 12(4), 505; https://doi.org/10.3390/biom12040505 - 26 Mar 2022

Viewed by 2772

Abstract

Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological signs of several tau-associated dementias. Types of neurons in the CNS are spared of tau pathology and are surrounded by a specialized form of extracellular matrix; called perineuronal nets (PNs). [...] Read more.

Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological signs of several tau-associated dementias. Types of neurons in the CNS are spared of tau pathology and are surrounded by a specialized form of extracellular matrix; called perineuronal nets (PNs). Aggrecan, the major PN proteoglycans, is suggested to mediate PNs neuroprotective function by forming an external shield preventing the internalization of misfolded tau. We recently demonstrated a correlation between aggrecan amount and the expression and phosphorylation of tau in a TauP310L-acan mouse model, generated by crossbreeding heterozygous aggrecan mice with a significant reduction of aggrecan and homozygous TauP301L mice. Neurodegenerative processes have been associated with changes of PN structure and protein signature. In this study, we hypothesized that the structure and protein expression of PNs in this TauP310L-acan mouse is regulated by tau. Immunohistochemical and biochemical analyses demonstrate that protein levels of PN components differ between TauP301L^HET-acan^WT and TauP301L^HET-acan^HET mice, accompanied by changes in the expression of protein phosphatase 2 A. In addition, tau can modulate PN components such as brevican. Co-immunoprecipitation experiments revealed a physical connection between PN components and tau. These data demonstrate a complex, mutual interrelation of tau and the proteoglycans of the PN. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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10 pages, 5464 KiB

Open AccessArticle

Multicenter ¹⁸F-PI-2620 PET for In Vivo Braak Staging of Tau Pathology in Alzheimer’s Disease

by Michael Rullmann, Matthias Brendel, Matthias L. Schroeter, Dorothee Saur, Johannes Levin, Robert G. Perneczky, Solveig Tiepolt, Marianne Patt, Andre Mueller, Victor L. Villemagne, Joseph Classen, Andrew W. Stephens, Osama Sabri, Henryk Barthel and on behalf of the German Imaging Initiative for Tauopathies (GII4T)

Biomolecules 2022, 12(3), 458; https://doi.org/10.3390/biom12030458 - 16 Mar 2022

Cited by 9 | Viewed by 3251

Abstract

Tau aggregates accumulate in the Alzheimer’s disease (AD) brain according to the established Braak staging scheme and spread from transentorhinal over limbic regions to the neocortex. To impact the management of AD patients, an in vivo tool for tau Braak staging is needed. [...] Read more.

Tau aggregates accumulate in the Alzheimer’s disease (AD) brain according to the established Braak staging scheme and spread from transentorhinal over limbic regions to the neocortex. To impact the management of AD patients, an in vivo tool for tau Braak staging is needed. First-generation tau tracers have limited performance in detecting early stages of tau. Therefore, we tested the corresponding capability of the next-generation tau tracer, ¹⁸F-PI-2620. We analyzed ¹⁸F-PI-2620 multicenter PET data from 37 beta-amyloid-positive AD dementia patients and those from 26 healthy controls. We applied kinetic modeling of the 0–60 min p.i. PET data using MRTM2 with the lower cerebellum as the reference region to extract Braak stage-dependent distribution volume ratios, whereas controls were used to define Braak stage PET positivity thresholds. Stage-dependent PET positivity widely followed the Braak scheme (except Braak stage III) presenting descending frequency of PET positivity from Braak I (43%), II (38%), III (49%), IV (35%), V (30%) to VI (14%). A strictly hierarchical model was met by 64% of AD dementia cases. Nineteen percent showed a hippocampal sparing tauopathy pattern. Thus, we could assign 87% to the six-stage hierarchical Braak model including tauopathy variants. ¹⁸F-PI-2620 PET appears to be able to perform Braak tau staging of AD in vivo. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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13 pages, 2143 KiB

Open AccessArticle

Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology

by Evelien Van Schoor, Mathieu Vandenbulcke, Valérie Bercier, Rik Vandenberghe, Julie van der Zee, Christine Van Broeckhoven, Markus Otto, Bernard Hanseeuw, Philip Van Damme, Ludo Van Den Bosch and Dietmar Rudolf Thal

Biomolecules 2022, 12(3), 440; https://doi.org/10.3390/biom12030440 - 12 Mar 2022

Cited by 5 | Viewed by 2900

Abstract

Recently, disease-associated variants of the TUBA4A gene were identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we present the neuropathological report of a patient with the semantic variant of primary progressive aphasia with a family history of Parkinsonism, [...] Read more.

Recently, disease-associated variants of the TUBA4A gene were identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we present the neuropathological report of a patient with the semantic variant of primary progressive aphasia with a family history of Parkinsonism, harboring a novel frameshift mutation c.187del (p.Arg64Glyfs*90) in TUBA4A. Immunohistochemistry showed abundant TAR DNA-binding protein 43 kDa (TDP-43) dystrophic neurite pathology in the frontal and temporal cortex and the dentate gyrus of the hippocampus, consistent with frontotemporal lobar degeneration (FTLD). The observed pathology pattern fitted best with that of FTLD-TDP Type C. qPCR showed the presence of mutant TUBA4A mRNA. However, no truncated TUBA4A was detected at the protein level. A decrease in total TUBA4A mRNA and protein levels suggests loss-of-function as a potential pathogenic mechanism. This report strengthens the idea that N-terminal TUBA4A mutations are associated with FTLD-TDP. These N-terminal mutations possibly exert their pathogenic effects through haploinsufficiency, contrary to C-terminal TUBA4A mutations which are thought to disturb the microtubule network via a dominant-negative mechanism. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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16 pages, 2424 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Evidence for Enhanced Efficacy of Passive Immunotherapy against Beta-Amyloid in CD33-Negative 5xFAD Mice

by Kathrin Gnoth, Stefanie Geissler, Julia Feldhaus, Nadine Taudte, Victoria Ilse, Sebastian Zürner, Sebastian Greiser, Ulf-Dietrich Braumann, Jens-Ulrich Rahfeld, Holger Cynis and Stephan Schilling

Biomolecules 2022, 12(3), 399; https://doi.org/10.3390/biom12030399 - 04 Mar 2022

Cited by 1 | Viewed by 2445

Abstract

Passive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). Among the different antibodies under development, those targeting post-translationally modified Aβ peptides might combine efficient reduction in beta-amyloid accompanied by lower sequestration in peripheral compartments and thus anticipated and [...] Read more.

Passive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). Among the different antibodies under development, those targeting post-translationally modified Aβ peptides might combine efficient reduction in beta-amyloid accompanied by lower sequestration in peripheral compartments and thus anticipated and reduced treatment-related side effects. In that regard, we recently demonstrated that the antibody-mediated targeting of isoD7-modified Aβ peptides leads to the attenuation of AD-like amyloid pathology in 5xFAD mice. In order to assess novel strategies to enhance the efficacy of passive vaccination approaches, we investigated the role of CD33 for Aβ phagocytosis in transgenic mice treated with an isoD7-Aβ antibody. We crossbred 5xFAD transgenic mice with CD33 knock out (CD33KO) mice and compared the amyloid pathology in the different genotypes of the crossbreds. The knockout of CD33 in 5xFAD mice leads to a significant reduction in Aβ plaques and concomitant rescue of behavioral deficits. Passive immunotherapy of 5xFAD/CD33KO showed a significant increase in plaque-surrounding microglia compared to 5xFAD treated with the antibody. Additionally, we observed a stronger lowering of Aβ plaque load after passive immunotherapy in 5xFAD/CD33KO mice. The data suggest an additive effect of passive immunotherapy and CD33KO in terms of lowering Aβ pathology. Hence, a combination of CD33 antagonists and monoclonal antibodies might represent a strategy to enhance efficacy of passive immunotherapy in AD. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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24 pages, 8564 KiB

Open AccessArticle

Spreading of Aggregated α-Synuclein in Sagittal Organotypic Mouse Brain Slices

by Buket Uçar, Nadia Stefanova and Christian Humpel

Biomolecules 2022, 12(2), 163; https://doi.org/10.3390/biom12020163 - 19 Jan 2022

Cited by 4 | Viewed by 2642

Abstract

The accumulation of α-synuclein (α-syn) in the brain plays a role in synucleinopathies and it is hypothesized to spread in a prion-like fashion between connected brain regions. In the present study, we aim to investigate this spreading in well-characterized sagittal organotypic whole brain [...] Read more.

The accumulation of α-synuclein (α-syn) in the brain plays a role in synucleinopathies and it is hypothesized to spread in a prion-like fashion between connected brain regions. In the present study, we aim to investigate this spreading in well-characterized sagittal organotypic whole brain slices taken from postnatal wild type (WT) and transgenic mice overexpressing human α-syn under the promoter of proteolipid protein (PLP). Collagen hydrogels were loaded with monomers of human α-syn, as well as human and mouse pre-formed fibrils (PFFs), to allow local application and slow release. The spreading of α-syn was evaluated in different brain regions by immunohistochemistry for total α-syn and α-syn phosphorylated at the serine129 position (α-syn-P). The application of human and mouse PFFs of α-syn caused the aggregation and spreading of α-syn-P in the brain slices, which was pronounced the most at the region of hydrogel application and surrounding striatum, as well as along the median forebrain bundle. The organotypic slices from transgenic mice showed significantly more α-syn pathology than those from WT mice. The present study demonstrates that seeding with α-syn PFFs but not monomers induced intracellular α-syn pathology, which was significantly more prominent in brain slices with α-syn overexpression. This is consistent with the prion-like spreading theory of α-syn aggregates. The sagittal whole brain slices characterized in this study carry the potential to be used as a novel model to study α-syn pathology. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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18 pages, 3172 KiB

Open AccessArticle

Inhibition of Polyglutamine Misfolding with D-Enantiomeric Peptides Identified by Mirror Image Phage Display Selection

by Pauline Elisabeth Kolkwitz, Jeannine Mohrlüder and Dieter Willbold

Biomolecules 2022, 12(2), 157; https://doi.org/10.3390/biom12020157 - 18 Jan 2022

Cited by 3 | Viewed by 1876

Abstract

Nine heritable diseases are known that are caused by unphysiologically elongated polyglutamine tracts in human proteins leading to misfolding, aggregation and neurodegeneration. Current therapeutic strategies include efforts to inhibit the expression of the respective gene coding for the polyglutamine-containing proteins. There are, however, [...] Read more.

Nine heritable diseases are known that are caused by unphysiologically elongated polyglutamine tracts in human proteins leading to misfolding, aggregation and neurodegeneration. Current therapeutic strategies include efforts to inhibit the expression of the respective gene coding for the polyglutamine-containing proteins. There are, however, concerns that this may interfere with the physiological function of the respective protein. We aim to stabilize the protein’s native conformation by D-enantiomeric peptide ligands to prevent misfolding and aggregation, shift the equilibrium between aggregates and monomers towards monomers and dissolve already existing aggregates into non-toxic and functional monomers. Here, we performed a mirror image phage display selection on the polyglutamine containing a fragment of the androgen receptor. An elongated polyglutamine tract in the androgen receptor causes spinal and bulbar muscular atrophy (SBMA). The selected D-enantiomeric peptides were tested for their ability to inhibit polyglutamine-induced androgen receptor aggregation. We identified D-enantiomeric peptide QF2D-2 (sqsqwstpqGkwshwprrr) as the most promising candidate. It binds to an androgen receptor fragment with 46 consecutive glutamine residues and decelerates its aggregation, even in seeded experiments. Therefore, QF2D-2 may be a promising drug candidate for SBMA treatment or even for all nine heritable polyglutamine diseases, since its aggregation-inhibiting property was shown also for a more general polyglutamine target. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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29 pages, 9758 KiB

Open AccessArticle

Surfactant Protein-G in Wildtype and 3xTg-AD Mice: Localization in the Forebrain, Age-Dependent Hippocampal Dot-like Deposits and Brain Content

by Anton Meinicke, Wolfgang Härtig, Karsten Winter, Joana Puchta, Bianca Mages, Dominik Michalski, Alexander Emmer, Markus Otto, Karl-Titus Hoffmann, Willi Reimann, Matthias Krause and Stefan Schob

Biomolecules 2022, 12(1), 96; https://doi.org/10.3390/biom12010096 - 07 Jan 2022

Cited by 3 | Viewed by 1789

Abstract

The classic surfactant proteins (SPs) A, B, C, and D were discovered in the lungs, where they contribute to host defense and regulate the alveolar surface tension during breathing. Their additional importance for brain physiology was discovered decades later. SP-G, a novel amphiphilic [...] Read more.

The classic surfactant proteins (SPs) A, B, C, and D were discovered in the lungs, where they contribute to host defense and regulate the alveolar surface tension during breathing. Their additional importance for brain physiology was discovered decades later. SP-G, a novel amphiphilic SP, was then identified in the lungs and is mostly linked to inflammation. In the brain, it is also present and significantly elevated after hemorrhage in premature infants and in distinct conditions affecting the cerebrospinal fluid circulation of adults. However, current knowledge on SP-G-expression is limited to ependymal cells and some neurons in the subventricular and superficial cortex. Therefore, we primarily focused on the distribution of SP-G-immunoreactivity (ir) and its spatial relationships with components of the neurovascular unit in murine forebrains. Triple fluorescence labeling elucidated SP-G-co-expressing neurons in the habenula, infundibulum, and hypothalamus. Exploring whether SP-G might play a role in Alzheimer’s disease (AD), 3xTg-AD mice were investigated and displayed age-dependent hippocampal deposits of β-amyloid and hyperphosphorylated tau separately from clustered, SP-G-containing dots with additional Reelin-ir—which was used as established marker for disease progression in this specific context. Semi-quantification of those dots, together with immunoassay-based quantification of intra- and extracellular SP-G, revealed a significant elevation in old 3xTg mice when compared to age-matched wildtype animals. This suggests a role of SP-G for the pathophysiology of AD, but a confirmation with human samples is required. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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17 pages, 2179 KiB

Open AccessArticle

Probing the Influence of Single-Site Mutations in the Central Cross-β Region of Amyloid β (1–40) Peptides

by Jacob Fritzsch, Alexander Korn, Dayana Surendran, Martin Krueger, Holger A. Scheidt, Kaustubh R. Mote, Perunthiruthy K. Madhu, Sudipta Maiti and Daniel Huster

Biomolecules 2021, 11(12), 1848; https://doi.org/10.3390/biom11121848 - 09 Dec 2021

Cited by 3 | Viewed by 2429

Abstract

Amyloid β (Aβ) is a peptide known to form amyloid fibrils in the brain of patients suffering from Alzheimer’s disease. A complete mechanistic understanding how Aβ peptides form neurotoxic assemblies and how they kill neurons has not yet been achieved. Previous analysis of [...] Read more.

Amyloid β (Aβ) is a peptide known to form amyloid fibrils in the brain of patients suffering from Alzheimer’s disease. A complete mechanistic understanding how Aβ peptides form neurotoxic assemblies and how they kill neurons has not yet been achieved. Previous analysis of various Aβ₄₀ mutants could reveal the significant importance of the hydrophobic contact between the residues Phe₁₉ and Leu₃₄ for cell toxicity. For some mutations at Phe₁₉, toxicity was completely abolished. In the current study, we assessed if perturbations introduced by mutations in the direct proximity of the Phe₁₉/Leu₃₄ contact would have similar relevance for the fibrillation kinetics, structure, dynamics and toxicity of the Aβ assemblies. To this end, we rationally modified positions Phe₂₀ or Gly₃₃. A small library of Aβ₄₀ peptides with Phe₂₀ mutated to Lys, Tyr or the non-proteinogenic cyclohexylalanine (Cha) or Gly₃₃ mutated to Ala was synthesized. We used electron microscopy, circular dichroism, X-ray diffraction, solid-state NMR spectroscopy, ThT fluorescence and MTT cell toxicity assays to comprehensively investigate the physicochemical properties of the Aβ fibrils formed by the modified peptides as well as toxicity to a neuronal cell line. Single mutations of either Phe₂₀ or Gly₃₃ led to relatively drastic alterations in the Aβ fibrillation kinetics but left the global, as well as the local structure, of the fibrils largely unchanged. Furthermore, the introduced perturbations caused a severe decrease or loss of cell toxicity compared to wildtype Aβ₄₀. We suggest that perturbations at position Phe₂₀ and Gly₃₃ affect the fibrillation pathway of Aβ₄₀ and, thereby, influence the especially toxic oligomeric species manifesting so that the region around the Phe₁₉/Leu₃₄ hydrophobic contact provides a promising site for the design of small molecules interfering with the Aβ fibrillation pathway. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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Review

Jump to: Research

27 pages, 14774 KiB

Open AccessReview

Natural Products from Plants and Algae for Treatment of Alzheimer’s Disease: A Review

by Jana Klose, Carola Griehl, Steffen Roßner and Stephan Schilling

Biomolecules 2022, 12(5), 694; https://doi.org/10.3390/biom12050694 - 12 May 2022

Cited by 11 | Viewed by 5328

Abstract

Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet [...] Read more.

Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. Here, we review current natural products that are either approved or are in testing for a treatment of neurodegeneration in AD. In addition to the most important compounds of plant origin, we also put special emphasis on compounds from algae, given their neuroprotective activity and their underlying mechanisms of neuroprotection. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

21 pages, 2081 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Parkin as a Molecular Bridge Linking Alzheimer’s and Parkinson’s Diseases?

by Frédéric Checler and Cristine Alves da Costa

Biomolecules 2022, 12(4), 559; https://doi.org/10.3390/biom12040559 - 09 Apr 2022

Cited by 4 | Viewed by 2996

Abstract

Alzheimer’s (AD) and Parkinson’s (PD) diseases are two distinct age-related pathologies that are characterized by various common dysfunctions. They are referred to as proteinopathies characterized by ubiquitinated protein accumulation and aggregation. This accumulation is mainly due to altered lysosomal and proteasomal clearing processes [...] Read more.

Alzheimer’s (AD) and Parkinson’s (PD) diseases are two distinct age-related pathologies that are characterized by various common dysfunctions. They are referred to as proteinopathies characterized by ubiquitinated protein accumulation and aggregation. This accumulation is mainly due to altered lysosomal and proteasomal clearing processes and is generally accompanied by ER stress disturbance, autophagic and mitophagic defects, mitochondrial structure and function alterations and enhanced neuronal cell death. Genetic approaches aimed at identifying molecular triggers responsible for familial forms of AD or PD have helped to understand the etiology of their sporadic counterparts. It appears that several proteins thought to contribute to one of these pathologies are also likely to contribute to the other. One such protein is parkin (PK). Here, we will briefly describe anatomical lesions and genetic advances linked to AD and PD as well as the main cellular processes commonly affected in these pathologies. Further, we will focus on current studies suggesting that PK could well participate in AD and thereby act as a molecular bridge between these two pathologies. In particular, we will focus on the transcription factor function of PK and its newly described transcriptional targets that are directly related to AD- and PD-linked cellular defects. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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16 pages, 1386 KiB

Open AccessReview

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

by Ferenc Bogár, Lívia Fülöp and Botond Penke

Biomolecules 2022, 12(3), 363; https://doi.org/10.3390/biom12030363 - 25 Feb 2022

Cited by 14 | Viewed by 3486

Abstract

Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other treatments that can stop the progression of NDDs. NDDs have many similarities and common [...] Read more.

Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other treatments that can stop the progression of NDDs. NDDs have many similarities and common pathways, e.g., formation of misfolded amyloid proteins, intra- and extracellular amyloid deposits, and chronic inflammation. Initially, the inflammation process has a cytoprotective function; however, an elevated and prolonged immune response has damaging effects and causes cell death. Neuroinflammation has been a target of drug development for treating and curing NDDs. Treatment of different NDDs with non-steroid anti-inflammatory drugs (NSAIDs) has failed or has given inconsistent results. The use of NSAIDs in diagnosed Alzheimer’s disease is currently not recommended. Sigma-1 receptor (Sig-1R) is a novel target for NDD drug development. Sig-1R plays a key role in cellular stress signaling, and it regulates endoplasmic reticulum stress and unfolded protein response. Activation of Sig-1R provides neuroprotection in cell cultures and animal studies. Clinical trials demonstrated that several Sig-1R agonists (pridopidine, ANAVEX3-71, fluvoxamine, dextrometorphan) and their combinations have a neuroprotective effect and slow down the progression of distinct NDDs. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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19 pages, 1939 KiB

Open AccessReview

Leukotriene Signaling as a Target in α-Synucleinopathies

by Katharina Strempfl, Michael S. Unger, Stefanie Flunkert, Andrea Trost, Herbert A. Reitsamer, Birgit Hutter-Paier and Ludwig Aigner

Biomolecules 2022, 12(3), 346; https://doi.org/10.3390/biom12030346 - 23 Feb 2022

Cited by 5 | Viewed by 2939

Abstract

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of [...] Read more.

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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19 pages, 1451 KiB

Open AccessReview

Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer’s Disease

by Muhammad Shahid Nadeem, Salman Hosawi, Sultan Alshehri, Mohammed M. Ghoneim, Syed Sarim Imam, Bibi Nazia Murtaza and Imran Kazmi

Biomolecules 2021, 11(11), 1635; https://doi.org/10.3390/biom11111635 - 04 Nov 2021

Cited by 16 | Viewed by 6155

Abstract

Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are neurodevelopmental and neurodegenerative disorders affecting two opposite ends of life span, i.e., childhood and old age. Both disorders pose a cumulative threat to human health, with the rate of incidences increasing considerably worldwide. In [...] Read more.

Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are neurodevelopmental and neurodegenerative disorders affecting two opposite ends of life span, i.e., childhood and old age. Both disorders pose a cumulative threat to human health, with the rate of incidences increasing considerably worldwide. In the context of recent developments, we aimed to review correlated symptoms and genetics, and overlapping aspects in the mechanisms of the pathogenesis of ASD and AD. Dementia, insomnia, and weak neuromuscular interaction, as well as communicative and cognitive impairments, are shared symptoms. A number of genes and proteins linked with both disorders have been tabulated, including MECP2, ADNP, SCN2A, NLGN, SHANK, PTEN, RELN, and FMR1. Theories about the role of neuron development, processing, connectivity, and levels of neurotransmitters in both disorders have been discussed. Based on the recent literature, the roles of FMRP (Fragile X mental retardation protein), hnRNPC (heterogeneous ribonucleoprotein-C), IRP (Iron regulatory proteins), miRNAs (MicroRNAs), and α-, β0, and γ-secretases in the posttranscriptional regulation of cellular synthesis and processing of APP (amyloid-β precursor protein) have been elaborated to describe the parallel and overlapping routes and mechanisms of ASD and AD pathogenesis. However, the interactive role of genetic and environmental factors, oxidative and metal ion stress, mutations in the associated genes, and alterations in the related cellular pathways in the development of ASD and AD needs further investigation. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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