Subcutaneous Administration of AMD3100 into Mice Models of Alzheimer’s Disease Ameliorated Cognitive Impairment, Reduced Neuroinflammation, and Improved Pathophysiological Markers

2020 ◽  
Vol 78 (2) ◽  
pp. 653-671
Author(s):  
Yuval Gavriel ◽  
Inna Rabinovich-Nikitin ◽  
Assaf Ezra ◽  
Becki Barbiro ◽  
Beka Solomon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cells ◽  
Bone Marrow ◽  
Cognitive Impairment ◽  
Combined Treatment ◽  
Amyloid Β ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
The Brain

Background: Alzheimer’s disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifest simultaneously, leading to cognitive impairment and death. Amyloid-β (Aβ) accumulation in the brain triggers the onset of AD, accompanied by neuroinflammatory response and pathological changes. The CXCR4/CXCL12 (SDF1) axis is one of the major signal transduction cascades involved in the inflammation process and regulation of homing of hematopoietic stem cells (HSCs) within the bone marrow niche. Inhibition of the axis with AMD3100, a reversible antagonist of CXCR4 mobilizes endogenous HSCs from the bone marrow into the periphery, facilitating the recruitment of bone marrow-derived microglia-like cells into the brain, attenuates the neuroinflammation process that involves release of excitotoxic markers such as TNFα, intracellular Ca2 +, and glutamate and upregulates monocarboxylate transporter 1, the major L-lactate transporter in the brain. Objective: Herein, we investigate if administration of a combination of AMD3100 and L-lactate may have beneficial effects in the treatment of AD. Methods: We tested the feasibility of the combined treatment for short- and long-term efficacy for inducing endogenous stem cells’ mobilization and attenuation of neuroinflammation in two distinct amyloid-β-induced AD mouse models. Results: The combined treatment did not demonstrate any adverse effects on the mice, and resulted in a significant improvement in cognitive/memory functions, attenuated neuroinflammation, and alleviated AD pathologies compared to each treatment alone. Conclusion: This study showed AMD3100’s beneficial effect in ameliorating AD pathogenesis, suggesting an alternative to the multistep procedures of transplantation of stem cells in the treatment of AD.

scholarly journals Electroacupuncture Improves Clearance of Amyloid-β through the Glymphatic System in the SAMP8 Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Pei-zhe Liang ◽  
Li Li ◽  
Ya-nan Zhang ◽  
Yan Shen ◽  
Li-li Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Control Group ◽  
Nissl Staining ◽  
Glymphatic System ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

Background. Memory loss and cognitive impairment characterize the neurodegenerative disorder, Alzheimer’s disease (AD). Amyloid-β (Aβ) is the key factor that triggers the course of AD, and reducing the deposition of Aβ in the brain has been considered as a potential target for the treatment of AD. In clinical and animal studies, electroacupuncture (EA) has been shown to be an effective treatment for AD. In recent years, substantial evidence has accumulated suggesting the important role of the glymphatic system in Aβ clearance. Objective. The purpose of this study was to explore whether EA modifies the accumulation of Aβ through the glymphatic system and may thus be applied to alleviate cognitive impairments. Methods. Seven-month-old SAMP8 mice were randomized into a control group (Pc) and an electroacupuncture group (Pe). Age-matched SAMR1 mice were used as normal controls (Rc). Mice in the Pe group were stimulated on Baihui (GV20) and Yintang (GV29) for 10 min and then pricked at Shuigou (GV26) for ten times. EA treatment lasted for 8 weeks. In each week, EA would be applied once a day for the first five consecutive days and ceased at the remaining two days. After EA treatment, Morris water maze (MWM) test was used to evaluate the cognitive function; HE and Nissl staining was performed to observe the brain histomorphology; ELISA, contrast-enhanced MRI, and immunofluorescence were applied to explore the mechanisms underlying EA effects from Aβ accumulation, glymphatic system function, reactivity of astrocytes, and AQP4 polarization, respectively. Results. This EA regime could improve cognition and alleviate neuropathological damage to brain tissue. And EA treatment might reduce Aβ accumulation, enhance paravascular influx in the glymphatic system, inhibit the reactivity of astrocytes, and improve AQP4 polarity. Conclusion. EA treatment might reduce Aβ accumulation from the brain via improving clearance performance of the glymphatic system and thereby alleviating cognitive impairment.

scholarly journals In vivo Characterization of Biochemical Variants of Amyloid-β in Subjects with Idiopathic Normal Pressure Hydrocephalus and Alzheimer’s Disease Neuropathological Change

2021 ◽  
pp. 1-10
Author(s):  
Sylwia Libard ◽  
Jochen Walter ◽  
Irina Alafuzoff
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Normal Pressure Hydrocephalus ◽  
Amyloid Β ◽  
Normal Pressure ◽  
Idiopathic Normal Pressure Hydrocephalus ◽  
Neuropathological Change ◽  
The Brain

Background: Stepwise occurrence of biochemically modified amyloid-β (Aβ) in the brain of subjects with Alzheimer’s disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aβ is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aβ are indeed also suffering from AD. Objective: We assessed the occurrence of biochemically modified Aβ variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia. Methods: We assessed Aβ proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry. Results: The pyroglutamylated Aβ (pyAβ) precedes the aggregation of phosphorylated Aβ (pAβ) during the AD neuropathological change progression; moreover, these modified variants of Aβ correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aβ aggregation that might be of significance for neurodegeneration leading to cognitive impairment. Conclusion: The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest.

Lipidomics and cognitive dysfunction – A Narrative review

2020 ◽  
Vol 45 (2) ◽  
Author(s):  
Arpita Chakraborty ◽  
Samir Kumar Praharaj ◽  
R. V. Krishnananda Prabhu ◽  
M. Mukhyaprana Prabhu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Vascular Dementia ◽  
Cognitive Dysfunction ◽  
Neurological Disorders ◽  
Brain Lipids ◽  
Complex Lipids ◽  
Functional Components ◽  
The Brain

AbstractBackgroundMore than half portion of the brain is formed by lipids. They play critical roles in maintaining the brain's structural and functional components. Any dysregulation in these brain lipids can lead to cognitive dysfunction which are associated with neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, vascular dementia etc. Studies have linked lipids with cognitive impairment. But not much has been studied about the complex brain lipids which might play a pivotal role in cognitive impairment. This review aims to highlight the lipidomic profiles in patients with cognitive dysfunction.ResultsForty-five articles were reviewed. These studies show alterations in complex lipids such as sphingolipids, phospholipids, glycolipids and sterols in brain in various neurological disorders such as vascular dementia, Parkinson's and Alzheimer's disease. However, the classes of fatty acids in these lipids involved are different across studies.ConclusionsThere is a need for targeted lipidomics analysis, specifically including sphingolipids in patients with neurodegenerative disorders so as to improve diagnostics as well as management of these disorders.

scholarly journals Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer’s disease

2021 ◽  
Author(s):  
Luis Enrique Arroyo-García ◽  
Arturo G. Isla ◽  
Yuniesky Andrade-Talavera ◽  
Hugo Balleza-Tapia ◽  
Raúl Loera-Valencia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mouse Model ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Gamma Rhythm ◽  
Fast Spiking

AbstractIn Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

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.

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.

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