scholarly journals Oral Amylin Treatment Reduces the Pathological Cascade of Alzheimer’s Disease in a Mouse Model

2021 ◽  
Vol 36 ◽  
pp. 153331752110128
Author(s):  
Hana Na ◽  
Hua Tian ◽  
Zhengrong Zhang ◽  
Qiang Li ◽  
Jack B. Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Calcium Binding ◽  
Oral Delivery ◽  
Amyloid Β ◽  
Enteric Neurons ◽  
Cyclin Dependent Kinase ◽  
Receptor Activity Modifying Proteins ◽  
The Brain ◽  
Cyclin Dependent Kinase 5

Intraperitoneal injection of amylin or its analog reduces Alzheimer’s disease (AD) pathology in the brains. However, self-injecting amylin analogs is difficult for patients due to cognitive deficits. This work aims to study the effects of amylin on the brain could be achieved by oral delivery as some study reported that amylin receptor may be present in the gastrointestinal tract. A 6-week course of oral amylin treatment reduced components of AD pathology, including the levels of amyloid-β, phosphorylated tau, and ionized calcium binding adaptor molecule 1. The treatment reduced active forms of cyclin-dependent kinase 5. Oral amylin treatment led to improvements in social deficit in AD mouse. Using immunofluorescence, we observed the amylin receptor complexed with the calcitonin receptor and receptor activity-modifying proteins in the enteric neurons. The study suggests the potential of the oral delivery of amylin analogs for the treatment of AD and other neurodegenerative diseases through enteric neurons.

Calpain-Mediated Alterations in Astrocytes Before and During Amyloid Chaos in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Bruna Schultz ◽  
Jéssica Taday ◽  
Leonardo Menezes ◽  
Anderson Cigerce ◽  
Marina C. Leite ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Damage ◽  
Amyloid Β ◽  
Mitogen Activated Protein Kinase ◽  
Cyclin Dependent Kinase ◽  
Calcium Dysregulation ◽  
Mitogen Activated Protein ◽  
Cyclin Dependent Kinase 5

One of the changes found in the brain in Alzheimer’s disease (AD) is increased calpain, derived from calcium dysregulation, oxidative stress, and/or neuroinflammation, which are all assumed to be basic pillars in neurodegenerative diseases. The role of calpain in synaptic plasticity, neuronal death, and AD has been discussed in some reviews. However, astrocytic calpain changes sometimes appear to be secondary and consequent to neuronal damage in AD. Herein, we explore the possibility of calpain-mediated astroglial reactivity in AD, both preceding and during the amyloid phase. We discuss the types of brain calpains but focus the review on calpains 1 and 2 and some important targets in astrocytes. We address the signaling involved in controlling calpain expression, mainly involving p38/mitogen-activated protein kinase and calcineurin, as well as how calpain regulates the expression of proteins involved in astroglial reactivity through calcineurin and cyclin-dependent kinase 5. Throughout the text, we have tried to provide evidence of the connection between the alterations caused by calpain and the metabolic changes associated with AD. In addition, we discuss the possibility that calpain mediates amyloid-β clearance in astrocytes, as opposed to amyloid-β accumulation in neurons.

scholarly journals Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1946
Author(s):  
Nitin Chitranshi ◽  
Ashutosh Kumar ◽  
Samran Sheriff ◽  
Veer Gupta ◽  
Angela Godinez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydrogen Bond ◽  
Virtual Screening ◽  
Cathepsin B ◽  
Amyloid Β ◽  
Proteolytic Degradation ◽  
Hydrogen Bond Acceptor ◽  
Starting Point ◽  
The Brain

Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.

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.

scholarly journals Diagnosing Alzheimer’s Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe

2021 ◽  
pp. 1-14
Author(s):  
Stefanie A.G. Black ◽  
Anastasiia A. Stepanchuk ◽  
George W. Templeton ◽  
Yda Hernandez ◽  
Tomoko Ota ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Blood Leukocytes ◽  
Peripheral Blood Mononuclear ◽  
The Brain

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

Cyclin-Dependent Kinase 5 Activator p25 Is Generated During Memory Formation and Is Reduced at an Early Stage in Alzheimer's Disease

2011 ◽  
Vol 70 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Olivia Engmann ◽  
Tibor Hortobágyi ◽  
Andrew J. Thompson ◽  
Jennifer Guadagno ◽  
Claire Troakes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Memory Formation ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase 5

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.

scholarly journals SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Tobias Gustavsson ◽  
Stina Syvänen ◽  
Paul O’Callaghan ◽  
Dag Sehlin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ex Vivo ◽  
Photon Emission ◽  
Amyloid Β ◽  
Emission Computed Tomography ◽  
Brain Uptake ◽  
Brain Distribution ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

Abstract Background Alzheimer’s disease (AD) immunotherapy with antibodies targeting amyloid-β (Aβ) has been extensively explored in clinical trials. The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ antibody variants – RmAb158, the recombinant murine version of BAN2401, which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients, and the bispecific RmAb158-scFv8D3, which has been engineered for enhanced brain uptake via transferrin receptor-mediated transcytosis. Methods A single intravenous injection of iodine-125 (125I)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice (tg-ArcSwe). In vivo single-photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 weeks. Activity in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with Aβ and CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with Aβ. Results Despite faster blood clearance, [125I]RmAb158-scFv8D3 displayed higher brain exposure than [125I]RmAb158 throughout the study. The brain distribution of [125I]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology, while [125I]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later times. Ex vivo autoradiography indicated greater vascular escape and parenchymal Aβ interactions for [125I]RmAb158-scFv8D3, whereas [125I]RmAb158 displayed retention and Aβ interactions in lateral ventricles. Conclusions The high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain imaging. Moreover, it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.

Recent progress on the role of GABAergic neurotransmission in the pathogenesis of Alzheimer’s disease

2016 ◽  
Vol 27 (4) ◽  
pp. 449-455 ◽  
Author(s):  
Ghulam Abbas ◽  
Wajahat Mahmood ◽  
Nurul Kabir
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gaba Receptor ◽  
Amyloid Β ◽  
Receptor Subtypes ◽  
Causative Role ◽  
Gabaergic Neurotransmission ◽  
Promising Target ◽  
The Brain

AbstractDespite their possible causative role, targeting amyloidosis, tau phosphorylation, acetylcholine esterase, glutamate, oxidative stress and mitochondrial metabolism have not yet led to the development of drugs to cure Alzheimer’s disease (AD). Recent preclinical and clinical reports exhibit a surge in interest in the role of GABAergic neurotransmission in the pathogenesis of AD. The interaction among GABAergic signaling, amyloid-β and acetylcholine is shown to affect the homeostasis between excitation (glutamate) and inhibition (GABA) in the brain. As a consequence, over-excitation leads to neurodegeneration (excitotoxicity) and impairment in the higher level functions. Previously, the glutamate arm of this balance received the most attention. Recent literature suggests that over-excitation is primarily mediated by dysfunctional GABA signaling and can possibly be restored by rectifying anomalous metabolism observed in the GABAergic neurons during AD. Additionally, neurogenesis and synaptogenesis have also been linked with GABAergic signaling. This association may provide a basis for the needed repair mechanism. Furthermore, several preclinical interventional studies revealed that targeting various GABA receptor subtypes holds potential in overcoming the memory deficits associated with AD. In conclusion, the recent scientific literature suggests that GABAergic signaling presents itself as a promising target for anti-AD drug development.

Sign in / Sign up

Export Citation Format

Share Document