scholarly journals Inter-Cohort Validation of SuStaIn Model for Alzheimer’s Disease

2021 ◽  
Vol 4 ◽  
Author(s):  
Damiano Archetti ◽  
Alexandra L. Young ◽  
Neil P. Oxtoby ◽  
Daniel Ferreira ◽  
Gustav Mårtensson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Setting ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Research Data ◽  
Training Set ◽  
Cross Sectional ◽  
Data Set ◽  
Test Sets

Alzheimer’s disease (AD) is a neurodegenerative disorder which spans several years from preclinical manifestations to dementia. In recent years, interest in the application of machine learning (ML) algorithms to personalized medicine has grown considerably, and a major challenge that such models face is the transferability from the research settings to clinical practice. The objective of this work was to demonstrate the transferability of the Subtype and Stage Inference (SuStaIn) model from well-characterized research data set, employed as training set, to independent less-structured and heterogeneous test sets representative of the clinical setting. The training set was composed of MRI data of 1043 subjects from the Alzheimer’s disease Neuroimaging Initiative (ADNI), and the test set was composed of data from 767 subjects from OASIS, Pharma-Cog, and ViTA clinical datasets. Both sets included subjects covering the entire spectrum of AD, and for both sets volumes of relevant brain regions were derived from T1-3D MRI scans processed with Freesurfer v5.3 cross-sectional stream. In order to assess the predictive value of the model, subpopulations of subjects with stable mild cognitive impairment (MCI) and MCIs that progressed to AD dementia (pMCI) were identified in both sets. SuStaIn identified three disease subtypes, of which the most prevalent corresponded to the typical atrophy pattern of AD. The other SuStaIn subtypes exhibited similarities with the previously defined hippocampal sparing and limbic predominant atrophy patterns of AD. Subject subtyping proved to be consistent in time for all cohorts and the staging provided by the model was correlated with cognitive performance. Classification of subjects on the basis of a combination of SuStaIn subtype and stage, mini mental state examination and amyloid-β1-42 cerebrospinal fluid concentration was proven to predict conversion from MCI to AD dementia on par with other novel statistical algorithms, with ROC curves that were not statistically different for the training and test sets and with area under curve respectively equal to 0.77 and 0.76. This study proves the transferability of a SuStaIn model for AD from research data to less-structured clinical cohorts, and indicates transferability to the clinical setting.

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

The Involvement of Post-Translational Modifications in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 313-335 ◽  
Author(s):  
Serena Marcelli ◽  
Massimo Corbo ◽  
Filomena Iannuzzi ◽  
Lucia Negri ◽  
Fabio Blandini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Modification ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Normal Function ◽  
Ageing Population ◽  
Covalent Bonds ◽  
Post Translational Modifications ◽  
Related Proteins

Background: Alzheimer's disease (AD) is a neurodegenerative disorder recognized as the most common cause of chronic dementia among the ageing population. AD is histopathologically characterized by progressive loss of neurons and deposits of insoluble proteins, primarily composed of amyloid-β pelaques and neurofibrillary tangles (NFTs). Methods: Several molecular processes contribute to the formation of AD cellular hallmarks. Among them, post-translational modifications (PTMs) represent an attractive mechanism underlying the formation of covalent bonds between chemical groups/peptides to target proteins, which ultimately result modified in their function. Most of the proteins related to AD undergo PTMs. Several recent studies show that AD-related proteins like APP, Aβ, tau, BACE1 undergo post-translational modifications. The effect of PTMs contributes to the normal function of cells, although aberrant protein modification, which may depend on many factors, can drive the onset or support the development of AD. Results: Here we will discuss the effect of several PTMs on the functionality of AD-related proteins potentially contributing to the development of AD pathology. Conclusion: We will consider the role of Ubiquitination, Phosphorylation, SUMOylation, Acetylation and Nitrosylation on specific AD-related proteins and, more interestingly, the possible interactions that may occur between such different PTMs.

scholarly journals Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna A. Lauer ◽  
Daniel Janitschke ◽  
Malena dos Santos Guilherme ◽  
Vu Thu Thuy Nguyen ◽  
Cornel M. Bachmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Lipid Homeostasis ◽  
Medical Surveillance ◽  
Shotgun Lipidomics ◽  
App Processing ◽  
Cognitive Improvement ◽  
The Impact

AbstractAlzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

scholarly journals NMR structure of the water soluble Aβ17–34 peptide

2014 ◽  
Vol 34 (6) ◽  
Author(s):  
Genadiy Fonar ◽  
Abraham O. Samson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nicotinic Acetylcholine Receptors ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Helical Structure ◽  
Nmr Structure ◽  
Water Soluble ◽  
Helical Conformation ◽  
Aβ Amyloid

Alzheimer's disease is the most common neurodegenerative disorder in the world. Its most significant symptoms are memory loss and decrease in cognition. Alzheimer's disease is characterized by aggregation of two proteins in the brain namely Aβ (amyloid β) and tau. Recent evidence suggests that the interaction of soluble Aβ with nAChR (nicotinic acetylcholine receptors) contributes to disease progression. In this study, we determine the NMR structure of an Aβ17–34 peptide solubilized by the addition of two glutamic acids at each terminus. Our results indicate that the Aβ peptide adopts an α-helical structure for residues 19–26 and 28–33. The α-helical structure is broken around residues S26, N27 and K28, which form a kink in the helical conformation. This α-helix was not described earlier in an aqueous solution without organic solvents, and at physiological conditions (pH 7). These data are in agreement with Aβ adopting an α-helical conformation in the membrane before polymerizing into amyloid β-sheets and provide insight into the intermediate state of Aβ in Alzheimer's disease.

scholarly journals Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models

2021 ◽  
Author(s):  
◽  
Rosemary Heathcott
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disease ◽  
Cell Line ◽  
Cholesterol Metabolism ◽  
Neurodegenerative Disorder ◽  
Heparan Sulphate ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Lysosomal Storage

<p>Heparan sulphate proteoglycans (HSPG) are central to numerous processes of the mammalian cell. The highly charged negative side chains of the heparan sulphate (HS) oligosaccharides are essential for the regulatory and structural functions of the proteoglycan. Synthetic HS compounds have potential therapeutic value due to their ability to mimic naturally occurring HS. Niemann-Pick disease type C (NPC) is a fatal childhood neurodegenerative disease with characteristic cholesterol and sphingolipid accumulation in the late endosome or lysosome. Alzheimer’s disease, another neurodegenerative disorder, shares alterations of cholesterol and amyloid β metabolism with NPC. In this study,a set of novel heparan sulphate compounds with a range of structures and oligosaccharide side groups with a variety of degrees of sulphation was investigated with regards to their effects on cholesterol and amyloid β metabolism in cell line models of these two diseases. Fluorescent staining of cholesterol and confocal microscopy showed highly sulphated compounds reduce the accumulation of cholesterol in the perinuclear lysosomal storage organelles in patient fibroblast cell lines. The compounds had no effect on secreted amyloid β levels or amyloid precursor protein levels in a neuronal cell line model of early onset Alzheimer’s disease. The mechanism of cholesterol reduction is unclear but may be related to a reduction in HSPG-associated endocytosis of LDL/cholesterol.</p>

scholarly journals Classification of Alzheimer’s Disease with and without Imagery Using Gradient Boosted Machines and ResNet-50

2019 ◽  
Vol 9 (9) ◽  
pp. 212 ◽  
Author(s):  
Lawrence Fulton ◽  
Diane Dolezel ◽  
Jordan Harrop ◽  
Yan Yan ◽  
Christopher Fulton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Family Planning ◽  
Prediction Accuracy ◽  
Network Models ◽  
Training Set ◽  
Clinical Dementia Rating ◽  
Cross Sectional ◽  
Term Care ◽  
Class Prediction

Background. Alzheimer’s is a disease for which there is no cure. Diagnosing Alzheimer’s disease (AD) early facilitates family planning and cost control. The purpose of this study is to predict the presence of AD using socio-demographic, clinical, and magnetic resonance imaging (MRI) data. Early detection of AD enables family planning and may reduce costs by delaying long-term care. Accurate, non-imagery methods also reduce patient costs. The Open Access Series of Imaging Studies (OASIS-1) cross-sectional MRI data were analyzed. A gradient boosted machine (GBM) predicted the presence of AD as a function of gender, age, education, socioeconomic status (SES), and a mini-mental state exam (MMSE). A residual network with 50 layers (ResNet-50) predicted the clinical dementia rating (CDR) presence and severity from MRI’s (multi-class classification). The GBM achieved a mean 91.3% prediction accuracy (10-fold stratified cross validation) for dichotomous CDR using socio-demographic and MMSE variables. MMSE was the most important feature. ResNet-50 using image generation techniques based on an 80% training set resulted in 98.99% three class prediction accuracy on 4139 images (20% validation set) at Epoch 133 and nearly perfect multi-class predication accuracy on the training set (99.34%). Machine learning methods classify AD with high accuracy. GBM models may help provide initial detection based on non-imagery analysis, while ResNet-50 network models might help identify AD patients automatically prior to provider review.

scholarly journals Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 232
Author(s):  
Antaripa Bhattacharya ◽  
Antonella Izzo ◽  
Nunzia Mollo ◽  
Filomena Napolitano ◽  
Adriana Limone ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Golgi Apparatus ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Laminin Receptor ◽  
Mitochondrial Network ◽  
App Trafficking ◽  
Healthy Control

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted Aβ in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the “typical” APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer’s disease.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

2020 ◽  
Vol 14 ◽  
Author(s):  
Antonio Munafò ◽  
Chiara Burgaletto ◽  
Giulia Di Benedetto ◽  
Marco Di Mauro ◽  
Rosaria Di Mauro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Drug Repositioning ◽  
Amyloid Β ◽  
Deep Understanding ◽  
Current Status ◽  
Age Related ◽  
Tnf Α

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

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