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 Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Jia ◽  
Juan Piña-Crespo ◽  
Yonghe Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Signal Transduction Pathway ◽  
Amyloid Β ◽  
Synaptic Loss ◽  
Cellular Processes ◽  
And Function ◽  
The Brain ◽  
Blood Brain Barrier Integrity

AbstractAlzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.

scholarly journals The glymphatic system and its role in the development of Alzheimer’s disease

2021 ◽  
Vol 8 (3) ◽  
pp. 14-21
Author(s):  
S. V. Vorobʼev ◽  
S. N. Yanishevskij
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Picture ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
Comprehensive Analysis ◽  
Synaptic Dysfunction ◽  
Glymphatic System ◽  
Neurodegenerative Pathology ◽  
The Brain

One of the main concepts explaining the development of Alzheimer’s disease is currently the amyloid theory. It was reliably established that the accumulation of the pathological protein amyloid β provokes the launch of a number of pathochemical reactions that ultimately lead to the development of synaptic dysfunction and the formation of cognitive disorders. The protein amyloid β is also synthesized in the brain of people who do not suffer from neurodegenerative pathology. Normally, it is actively removed from the brain. However, the exact mechanisms for maintaining its clearance are not established. The recently discovered glymphatic system claims to be such a component. The present review provides a comprehensive analysis of suggestions that the development of glymphatic system dysfunction contributes to the accumulation of amyloid β and the development of the clinical picture of Alzheimer›s disease.

scholarly journals Neurogranin and Neuronal Pentraxin Receptor as Synaptic Dysfunction Biomarkers in Alzheimer’s Disease

2021 ◽  
Vol 10 (19) ◽  
pp. 4575
Author(s):  
Maciej Dulewicz ◽  
Agnieszka Kulczyńska-Przybik ◽  
Agnieszka Słowik ◽  
Renata Borawska ◽  
Barbara Mroczko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Synaptic Proteins ◽  
Synaptic Dysfunction ◽  
Enzyme Linked Immunosorbent Assay ◽  
Synaptic Loss ◽  
Neuronal Pentraxin ◽  
The Relationship ◽  
Xmap Technology

Synaptic loss and dysfunction are one of the earliest signs of neurodegeneration associated with cognitive decline in Alzheimer’s disease (AD). It seems that by assessing proteins related to synapses, one may reflect their dysfunction and improve the understanding of neurobiological processes in the early stage of the disease. To our best knowledge, this is the first study that analyzes the CSF concentrations of two synaptic proteins together, such as neurogranin (Ng) and neuronal pentraxins receptor (NPTXR) in relation to neurochemical dementia biomarkers in Alzheimer’s disease. Methods: Ng, NPTXR and classical AD biomarkers concentrations were measured in the CSF of patients with AD and non-demented controls (CTRL) using an enzyme-linked immunosorbent assay (ELISA) and Luminex xMAP technology. Results: The CSF level of Ng was significantly higher, whereas the NPTXR was significantly lower in the AD patients than in cognitively healthy controls. As a first, we calculated the NPTXR/Ng ratio as an indicator of synaptic disturbance. The patients with AD presented a significantly decreased NPTXR/Ng ratio. The correlation was observed between both proteins in the AD and the whole study group. Furthermore, the relationship between the Ng level and pTau181 was found in the AD group of patients. Conclusions: The Ng and NPTXR concentrations in CSF are promising synaptic dysfunction biomarkers reflecting pathological changes in AD.

scholarly journals Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2576-2593 ◽  
Author(s):  
Ian F Harrison ◽  
Ozama Ismail ◽  
Asif Machhada ◽  
Niall Colgan ◽  
Yolanda Ohene ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Disease Model ◽  
Amyloid Β ◽  
The Novel ◽  
Glymphatic System ◽  
Protein Clearance ◽  
Glymphatic Pathway ◽  
The Brain

Abstract The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer’s disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer’s disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer’s disease, and possibly other neurodegenerative diseases alike.

Recent Advances in Nanotechnology: A Novel Therapeutic System for the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 21 (14) ◽  
pp. 1144-1151
Author(s):  
Pallavi Singh Chauhan ◽  
Dhananjay Yadav ◽  
Bhupendra Koul ◽  
Yugal Kishore Mohanta ◽  
Jun-O Jin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Collaborative Research ◽  
Early Stage ◽  
Amyloid Β ◽  
Plaque Formation ◽  
Therapeutic System ◽  
Root Cause ◽  
Random Coils ◽  
The Brain

: A amyloid-β (Aβ) plaque formation in the brain is known to be the root cause of Alzheimer’s disease (AD), which affects the behavior, memory, and cognitive ability in humans. The brain starts undergoing changes several years before the actual appearance of the symptoms. Nanotechnology could prove to be an alternative strategy for treating the disease effectively. It encompasses the diagnosis as well as the therapeutic aspect using validated biomarkers and nano-based drug delivery systems, respectively. A nano-based therapy may provide an alternate strategy, wherein one targets the protofibrillar amyloid-β (Aβ) structures, and this is followed by their disaggregation as random coils. Conventional/routine drug therapies are inefficient in crossing the blood-brain barrier; however, this hurdle can be overcome with the aid of nanoparticles. The present review highlights the various challenges in the diagnosis and treatment of AD. Meticulous and collaborative research using nanotherapeutic systems could provide remarkable breakthroughs in the early-stage diagnosis and therapy of AD.

ANTI-TAU TRIALS FOR ALZHEIMER’S DISEASE: A REPORT FROM THE EU/US/CTAD TASK FORCE

2019 ◽  
pp. 1-7
Author(s):  
J. Cummings ◽  
K. Blennow ◽  
K. Johnson ◽  
M. Keeley ◽  
R.J. Bateman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Task Force ◽  
Phase 1 ◽  
Amyloid Β ◽  
Imaging Studies ◽  
And Function ◽  
The Brain ◽  
The Eu

Efforts to develop effective disease-modifying treatments for Alzheimer’s disease (AD) have mostly targeted the amyloid β (Aβ) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aβ protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.

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 Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 957
Author(s):  
Brad T. Casali ◽  
Erin G. Reed-Geaghan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cells ◽  
Expression Patterns ◽  
Brain Parenchyma ◽  
Primary Role ◽  
And Function ◽  
Inflammatory Milieu ◽  
The Brain ◽  
Homeostatic State

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD.

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 Astrocytes and neuroinflammation in Alzheimer's disease

2014 ◽  
Vol 42 (5) ◽  
pp. 1321-1325 ◽  
Author(s):  
Emma C. Phillips ◽  
Cara L. Croft ◽  
Ksenia Kurbatskaya ◽  
Michael J. O’Neill ◽  
Michael L. Hutton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Responses ◽  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Amyloid Β Peptide ◽  
Substantial Evidence ◽  
Models Of Disease ◽  
Opposing Effects

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

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