Circulatory GSK-3β: Blood-Based Biomarker and Therapeutic Target for Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Shiwani Kumari ◽  
Ambica Singh ◽  
Abhinay Kumar Singh ◽  
Yudhishthir Yadav ◽  
Swati Bajpai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Memory Loss ◽  
Amyloid Β ◽  
Clear Understanding ◽  
Dependent Manner ◽  
Brain Disorder ◽  
Gsk 3Β ◽  
Dose Dependent

Background: Alzheimer’s disease (AD) is the progressive brain disorder which degenerates brain cells connection and causes memory loss. Although AD is irreversible, it is not impossible to arrest or slow down the progression of the disease. However, this would only be possible if the disease is diagnosed at an early stage, and early diagnosis requires clear understanding of the pathogenesis at molecular level. Overactivity of GSK-3β and p53 accounts for tau hyperphosphorylation and the formation of amyloid-β plaques. Objective: Here, we explored GSK-3β and p53 as blood-based biomarkers for early detection of AD. Methods: The levels of GSK-3β, p53, and their phosphorylated states were measured using surface plasmon resonance and verified using western blot in serum from AD, mild cognitive impairment (MCI), and geriatric-control (GC) subjects. The neurotoxic SH-SY5Y cell line was treated with antioxidant Emblica Officinalis (EO) for rescue effect. Results: GSK-3β, p53, and their phosphorylated states were significantly over expressed (p >  0.001) in AD and MCI compared to GC and can differentiate AD and MCI from GC. The expression level of GSK-3β and p53 proteins were found to be downregulated in a dose-dependent manner after the treatment with EO in amyloid-b-induced neurotoxic cells. Conclusion: These proteins can serve as potential blood markers for the diagnosis of AD and EO can suppress their level. This work has translational value and clinical utility in the future.

scholarly journals Alzheimer’s disease: many failed trials, so where do we go from here?

2020 ◽  
Vol 68 (6) ◽  
pp. 1135-1140 ◽  
Author(s):  
Allison Bethanne Reiss ◽  
Amy D Glass ◽  
Thomas Wisniewski ◽  
Benjamin Wolozin ◽  
Irving H Gomolin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Memory Loss ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Brain Disorder ◽  
The Central Nervous System ◽  
Progressive Cognitive Impairment

Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid β and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.

scholarly journals Early Detection of MCI

2020 ◽  
Vol 9 (1) ◽  
pp. 1928-1931
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Learning Algorithm ◽  
Early Stage ◽  
Memory Loss ◽  
Brain Disorder ◽  
Clinical Impairment ◽  
Short Memory ◽  
Last Stage ◽  
The Brain

Dementia is the brain disorder, that effects the mental cognitive function. Dementia has different stages. when the person is in the early stage they have short memory, losing or misplacing things, the person have more memory loss in moderate stage. During last stage patient completely depends on other for everyday activities. MCI has come to be recognized as an intermediate state of clinical impairment where an individual has mild cognitive symptoms but generally continue to function normally in the community. it is important to determine AD at an earlier stage which is Mild Cognitive Impairment (MCI). Toxic changes may start in the brain at the beginning stage of Alzheimer's disease. MRI Images are used to detect disease at the earlies stage. Wavelet Transform is applied on the MRI Images followed by any feature selection. Machine learning algorithm is used to make prediction. This paper goes through all those studies and techniques used by scientists to unravel the progression of Alzheimer's disease.

scholarly journals Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer's disease progression.

2021 ◽  
Author(s):  
Dong Won Kim ◽  
Kevin Tu ◽  
Alice Wei ◽  
Ashley Lau ◽  
Anabel Gonzalez-Gil ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Amyloid Β ◽  
Disease Stage ◽  
Dependent Manner ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Human Orthologue ◽  
Late Stages

It is unknown whether specific microglia are selectively induced by amyloid-β(Aβ), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both Aβ and tau pathologies during Alzheimer's disease (AD). We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of the human orthologue of Siglecg is progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both Aβ and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.

scholarly journals Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1802
Author(s):  
Enrique Armijo ◽  
George Edwards ◽  
Andrea Flores ◽  
Jorge Vera ◽  
Mohammad Shahnawaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cerebral Atrophy ◽  
Brain Inflammation ◽  
Neural Precursors ◽  
Model Of Alzheimer’S Disease ◽  
Induced Pluripotent

Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

scholarly journals Case of early-onset Alzheimer’s disease with atypical manifestation

2021 ◽  
Vol 34 (1) ◽  
pp. e100283
Author(s):  
Lin Zhu ◽  
Limin Sun ◽  
Lin Sun ◽  
Shifu Xiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Manifestation ◽  
Early Onset ◽  
Short Term Memory ◽  
Brain Mri ◽  
Memory Loss ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Fluent Aphasia

Short-term memory decline is the typical clinical manifestation of Alzheimer’s disease (AD). However, early-onset AD usually has atypical symptoms and may get misdiagnosed. In the present case study, we reported a patient who experienced symptoms of memory loss with progressive non-fluent aphasia accompanied by gradual social withdrawal. He did not meet the diagnostic criteria of AD based on the clinical manifestation and brain MRI. However, his cerebrospinal fluid examination showed a decreased level of beta-amyloid 42, and increased total tau and phosphorylated tau. Massive amyloid β-protein deposition by 11C-Pittsburgh positron emission tomography confirmed the diagnosis of frontal variant AD. This case indicated that early-onset AD may have progressive non-fluent aphasia as the core manifestation. The combination of individual and precision diagnosis would be beneficial for similar cases.

scholarly journals Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3261
Author(s):  
Xiao Liu ◽  
Qian Zhou ◽  
Jia-He Zhang ◽  
Xiaoying Wang ◽  
Xiumei Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Disease Model ◽  
Amyloid Β ◽  
Brain Lesions ◽  
Synaptic Dysfunction ◽  
Synaptic Loss ◽  
And Function ◽  
The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

Targeted delivery of montelukast for treatment of Alzheimer’s disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Ashok K. Datusalia ◽  
Gurpreet Singh ◽  
Nikita Yadav ◽  
Sachin Gaun ◽  
Moumita Manik ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Targeted Delivery ◽  
Symptomatic Relief ◽  
Memory Loss ◽  
Amyloid Β ◽  
Lessons Learned ◽  
Nano Structure ◽  
Substantial Impact ◽  
Structure Lipid

: Alzheimer’s disease (AD) is one of the most common neurodegenerative disease, which affect millions of people worldwide. Accumulation of amyloid-β plaques and hyperphosphorylated neurofibrillary tangles are the key mechanisms involved in the etiopathogenesis of AD, characterized by memory loss and behavioural changes. Effective therapies targeting AD pathogenesis are limited, making it the largest unmet clinical need. Unfortunately, the available drugs provide symptomatic relief and primary care, with no substantial impact on the disease pathology. However, in recent years researchers are working hard on several potential therapeutic targets to combat disease pathogenesis and few drugs have also reached clinical trials. In addition, drugs are being repurposed both in the preclinical and clinical studies for the treatment of AD. For instance, montelukast is most commonly used leukotriene receptor antagonist, for treating asthma and seasonal allergy. Its leukotriene antagonistic action can also be beneficial for the reduction of detrimental effects of leukotriene against neuro-inflammation, an hallmark feature of AD. The available marketed formulations of montelukast present challenges such as poor bioavailability and reduced uptake, reflecting the lack of effectiveness of its desired action in the CNS. While on the other side targeted drug delivery is a satisfactory approach to surpass the challenges associated with the therapeutic agents. This review will discuss the enhancement of montelukast treatment efficacy and its access to CNS, by using new approaches like nano-formulation, nasal gel, solid lipid formulation, nano-structure lipid carrier (NSLC), highlighting lessons learned to target AD pathologies and hurdles that persist.

MR Brain Screening using Optimization Techniques – A survey

2021 ◽  
Vol 17 ◽  
Author(s):  
Chitradevi D ◽  
Prabha S.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cell Loss ◽  
Optimization Techniques ◽  
Amyloid Β Protein ◽  
The Brain ◽  
Brain Tissues

Background: Alzheimer’s disease (AD) is associated with Dementia, and it is also a memory syndrome in the brain. It affects the brain tissues and causes major changes in day-to-day activities. Aging is a major cause of Alzheimer's disease. AD is characterized by two pathological hallmarks as, Amyloid β protein and neurofibrillary tangles of hyperphosphorylated tau protein. The imaging hallmarks for Alzheimer’s disease are namely, swelling, shrinkage of brain tissues due to cell loss, and atrophy in the brain due to protein dissemination. Based on the survey, 60% to 80% of dementia patients belong to Alzheimer’s disease. Introduction: AD is now becoming an increasing and important brain disease. The goal of AD pathology is to cause changes/damage in brain tissues. Alzheimer's disease is thought to begin 20 years or more before symptoms appear, with tiny changes in the brain that are undetectable to the person affected. The changes in a person's brain after a few years are noticeable through symptoms such as language difficulties and memory loss. Neurons in different parts of the brain have detected symptoms such as cognitive impairments and learning disabilities. In this case, neuroimaging tools are necessary to identify the development of pathology which relates to the clinical symptoms. Methods: Several approaches have been tried during the last two decades for brain screening to analyse AD with the process of pre-processing, segmentation and classification. Different individual such as Grey Wolf optimization, Lion Optimization, Ant Lion Optimization and so on. Similarly, hybrid optimization techniques are also attempted to segment the brain sub-regions which helps in identifying the bio-markers to analyse AD. Conclusion: This study discusses a review of neuroimaging technologies for diagnosing Alzheimer's disease, as well as the discovery of hallmarks for the disease and the methodologies for finding hallmarks from brain images to evaluate AD. According to the literature review, most of the techniques predicted higher accuracy (more than 90%), which is beneficial for assessing and screening neurodegenerative illness, particularly Alzheimer's disease.

PET Imaging of Tau Pathology and Amyloid-β, and MRI for Alzheimer’s Disease Feature Fusion and Multimodal Classification

2021 ◽  
pp. 1-18
Author(s):  
Mehdi Shojaie ◽  
Solale Tabarestani ◽  
Mercedes Cabrerizo ◽  
Steven T. DeKosky ◽  
David E. Vaillancourt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Feature Selection ◽  
Mutual Information ◽  
Feature Fusion ◽  
Early Stage ◽  
Model Performance ◽  
Amyloid Β ◽  
Feature Ranking ◽  
Promising Tool

Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to capture the redundancy and complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition.

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