Aminotransferase Levels and Silymarin in de novo Tacrine-Treated Patients with Alzheimer’s Disease

1999 ◽  
Vol 10 (3) ◽  
pp. 181-185 ◽  
Author(s):  
H. Allain ◽  
S. Schück ◽  
S. Lebreton ◽  
A. Strenge-Hesse ◽  
W. Braun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo

scholarly journals Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Marcus O. W. Grimm ◽  
Sven Grösgen ◽  
Tatjana L. Rothhaar ◽  
Verena K. Burg ◽  
Benjamin Hundsdörfer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Physiological Function ◽  
Proteolytic Processing ◽  
Sphingolipid Metabolism ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Coa Transferase ◽  
Key Enzyme

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipidde novosynthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic ADpostmortembrains, suggesting that SPT is involved in AD pathology.

scholarly journals Microtubule assembly by soluble tau impairs vesicle endocytosis and excitatory neurotransmission via dynamin sequestration in Alzheimer's disease synapse model

2021 ◽  
Author(s):  
Tetsuya Hori ◽  
Kohgaku Eguchi ◽  
Han-Ying Wang ◽  
Tomohiro Miyasaka ◽  
Laurent Guillaud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Microtubule Assembly ◽  
Pleckstrin Homology Domain ◽  
Endocytic Protein ◽  
Brainstem Slices ◽  
Excitatory Neurotransmission ◽  
Synapse Model ◽  
Activity Dependent

Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer's disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in brainstem slices. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10-20 μM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin-1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission.

scholarly journals Difficult case of a rare form of familial Alzheimer’s disease with PSEN1 P117L mutation

2018 ◽  
Vol 11 (1) ◽  
pp. e226664
Author(s):  
Ana Luísa Rocha ◽  
Andreia Costa ◽  
Maria Carolina Garrett ◽  
Joana Meireles
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
De Novo ◽  
Spastic Paraparesis ◽  
Difficult Case ◽  
Diagnostic Challenge ◽  
Subsequent Investigation ◽  
Neurology Clinic ◽  
Upper Limb Paresis

Less than 10% of Alzheimer’s disease (AD) cases are familial. Presenilin-1 (PSEN1) mutations are the most frequent aetiology and may be associated to atypical neurological manifestations. We report the case of a 27-year-old right-handed man, ensuing with mild cognitive impairment, motor discoordination and axial myoclonus after a parachute accident. At age 32 he was referred to our neurology clinic, presenting cognitive impairment, cerebellar syndrome, axial myoclonus and hypomimia, without other signs of parkinsonism. Because of absence of family history, he was worked up along the line of spinal ataxic disorders. Later, he developed pseudobulbar affect, cognitive deterioration, right upper limb paresis and spastic paraparesis. Subsequent investigation identified a PSEN1 P117L mutation and the diagnosis of autosomal dominant AD was made. This case illustrates the diagnostic challenge imposed by atypical presentation of de novo PSEN1 mutation, leading to unnecessary investigation. Genetic study might be essential for defining the diagnosis.

scholarly journals The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease

2019 ◽  
Vol 25 (40) ◽  
pp. 5578-5587 ◽  
Author(s):  
Claus Desler ◽  
Meryl S. Lillenes ◽  
Tone Tønjum ◽  
Lene Juel Rasmussen
Keyword(s):  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
De Novo ◽  
Oxygen Species ◽  
De Novo Synthesis ◽  
Atp Production ◽  
Essential Phospholipids

The current molecular understanding of Alzheimer’s disease (AD) has still not resulted in successful interventions. Mitochondrial dysfunction of the AD brain is currently emerging as a hallmark of this disease. One mitochondrial function often affected in AD is oxidative phosphorylation responsible for ATP production, but also for production of reactive oxygen species (ROS) and for the de novo synthesis of pyrimidines. This paper reviews the role of mitochondrial produced ROS and pyrimidines in the aetiology of AD and their proposed role in oxidative degeneration of macromolecules, synthesis of essential phospholipids and maintenance of mitochondrial viability in the AD brain.

scholarly journals Microtubule affinity–regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration

2020 ◽  
Vol 295 (50) ◽  
pp. 17138-17147
Author(s):  
Toshiya Oba ◽  
Taro Saito ◽  
Akiko Asada ◽  
Sawako Shimizu ◽  
Koichi M. Iijima ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Elevated Risk ◽  
Protein Tau ◽  
Function Mechanism ◽  
Total Tau ◽  
Oligomeric Forms

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.

scholarly journals Deep Learning in Brain MRI: Effect of Data Leakage Due to Slice-level Split Using 2D Convolutional Neural Networks

2021 ◽  
Author(s):  
Ekin Yagis ◽  
Selamawet Workalemahu Atnafu ◽  
Alba García Seco de Herrera ◽  
Chiara Marzi ◽  
Marco Giannelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Neural Networks ◽  
Alzheimer's Disease ◽  
Convolutional Neural Networks ◽  
De Novo ◽  
Neurological Diseases ◽  
Brain Mri ◽  
Progression Markers ◽  
Magnetic Resonance Imaging Mri

Abstract In recent years, 2D convolutional neural networks (CNNs) have been extensively used for the diagnosis of neurological diseases from magnetic resonance imaging (MRI) data due to their potential to discern subtle and intricate patterns. Despite the high performances reported in numerous studies, developing CNN models with good generalization abilities is still a challenging task due to possible data leakage introduced during cross-validation (CV). In this study, we quantitatively assessed the effect of a data leakage caused by 3D MRI data splitting based on a 2D slice-level using three 2D CNN models for the classification of patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our experiments showed that slice-level CV erroneously boosted the average slice level accuracy on the test set by 30% on Open Access Series of Imaging Studies (OASIS), 29% on Alzheimer’s Disease Neuroimaging Initiative (ADNI), 48% on Parkinson's Progression Markers Initiative (PPMI) and 55% on a local de-novo PD Versilia dataset. Further tests on a randomly labeled OASIS-derived dataset produced about 96% of (erroneous) accuracy (slice-level split) and 50% accuracy (subject-level split), as expected from a randomized experiment. Overall, the extent of the effect of an erroneous slice-based CV is severe, especially for small datasets.

scholarly journals Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

2020 ◽  
Author(s):  
Michael J. Lucas ◽  
Henry S. Pan ◽  
Eric J. Verbeke ◽  
Lauren J. Webb ◽  
David W. Taylor ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Amyloid Β ◽  
Mesoporous Silicas ◽  
Aggregation Kinetics ◽  
Central Feature ◽  
Relative Population ◽  
Aβ Fibrils

AbstractThe aggregation of Amyloid-β (Aβ) is associated with the onset of Alzheimer’s Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of Aβ1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from Aβ1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Aβ1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of Aβ1-40 and other amyloidogenic proteins.Significance StatementA major challenge in understanding the progression of Alzheimer’s Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-β (Aβ). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that Aβ fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge this gap, we used surface-functionalized mesoporous silicas to influence the formation of Aβ1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of Aβ fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific Aβ polymorphs.

PET/MRI Delivers Multimodal Brain Signature in Alzheimer’s Disease with De Novo PSEN1 Mutation

2021 ◽  
Vol 18 ◽  
Author(s):  
Gayane Aghakhanyan ◽  
Dorothee Saur ◽  
Michael Rullmann ◽  
Christopher M. Weise ◽  
Matthias L. Schroeter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Diffusion Tensor ◽  
Molecular Genetic ◽  
Pathogenic Variant ◽  
Stage Iii ◽  
Braak Stage ◽  
Subcortical Structures ◽  
Functional Brain

Background: Little is known so far about the brain phenotype and the spatial interplay of different Alzheimer’s disease (AD) biomarkers with structural and functional brain connectivity in the early phase of autosomal-dominant AD (ADAD). Multimodal PET/MRI might be suitable to fill this gap. Material and Methods: We presented a 31-year-old male patient without a family history of de- mentia with progressive worsening of memory and motor function. Two separate sessions of 3T PET/MRI acquisitions were arranged with the ß-amyloid tracer [18F]Florbetaben and the second-- generation tau tracer [18F]PI-2620. Simultaneously acquired MRI consisted of high-resolution 3D T1, diffusion-tensor imaging (DTI), and resting-state fMRI. PET/MRI data were compared with ten age-matched healthy controls. Results: Widespread β-amyloid depositions were found in cortical regions, and striatum (Thal stage III) along with tau pathology restricted to the mesial-temporal structures (Braak stage III/IV). Volumetric/shape analysis of subcortical structures revealed atrophy of the hippocampal-amygdala complex. In addition, cortical thinning was detected in the right middle temporal pole. Alterations of multiple DTI indices were noted in the major white matter fiber bundles, together with disrup- tion of default mode and sensory-motor network functional connectivity. Molecular genetic analy- sis by next-generation sequencing revealed a heterozygote missense pathogenic variant of the PSEN1 (Met233Val). Conclusion: Multimodal PET/MR imaging is able to deliver, in a one-stop-shop approach, an ar- ray of molecular, structural and functional brain information in AD due to de novo pathogenic variant, which can be studied for spatial interplay and might provide a rationale for initiating an- ti-amyloid/tau therapeutic approaches.

De Novo PS1 Mutation (Pro436Gln) in a Very Early-Onset Posterior Variant of Alzheimer’s Disease Associated with Spasticity: A Case Report

2021 ◽  
pp. 1-6
Author(s):  
Pablo Agüero ◽  
María José Sainz ◽  
Raquel Téllez ◽  
Isabel Lorda ◽  
Almudena Ávila ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Clinical Phenotype ◽  
Brain Mri ◽  
Amyloid Β ◽  
Strong Impact ◽  
Amyloid Pet ◽  
Posterior Cortex ◽  
Cerebrospinal Fluid Biomarkers

We report a patient with sporadic Alzheimer’s disease with onset in his twenties found to carry the de novo Pro436Gln mutation in the presenilin 1 gene (PS1). Clinical phenotype featured a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. Brain MRI and FDG-PET scans revealed severe parieto-occipital atrophy/hypometabolism. Cerebrospinal fluid biomarkers showed a decrease in Aβ 42 level and Aβ 42/40 ratio, increased phospho-tau, and normal total tau. Amyloid PET identified a very high burden of amyloid-β neuritic plaques in the posterior cortex. Similarities between this and two previously reported cases with this variant support that this mutation has a very strong impact on the clinical phenotype and is consistently associated with spasticity.

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