scholarly journals Administration of Mucuna Beans (Mucuna Pruriences (L.) DC. Var. Utilis) Improves Cognition and Neuropathology of 3×Tg-AD Mice

2021 ◽  
Author(s):  
Fumiko Konishi ◽  
Tadasu Furusho ◽  
Yoshiyuki Soeda ◽  
Jun Yamauchi ◽  
Shoko Kobayashi ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Control Group ◽  
Phosphorylated Tau ◽  
Aβ Oligomers ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Hyperphosphorylated Tau Protein ◽  
Ad Prevention ◽  
The Brain

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-beta peptides (Aβ) resulting in senile plaques and intracellular hyperphosphorylated tau protein resulting in neurofibrillary tangles (NFTs). Mucuna beans (Mucuna pruriences (L.) DC. var. utilis) are unique plants containing 3%–9% L-3,4-dihydroxyphenylalanine (L-DOPA). Here we investigated the effect of the administration of Mucuna beans on AD prevention by feeding triple-transgenic mice (3×Tg-AD mice) with a diet containing Mucuna beans for 13 months. The levels of Aβ oligomers and detergent-insoluble phosphorylated tau decreased in the brain of mice fed with Mucuna beans (Mucuna group) compared to those of the Control group. Aβ accumulation and phosphorylated tau accumulation in the brain in the Mucuna group were also reduced. In addition, administration of Mucuna beans improved cognitive function. These results suggest that administration of Mucuna beans may have a preventive effect on AD development in 3×Tg-AD mice.

Active Immunotherapy with 12-mer Aβ1-42-like Assembly Vaccine Shows Efficacy in Aged 3×Tg-AD Mice

2020 ◽  
Vol 20 ◽  
Author(s):  
Hao Fang ◽  
Guo Zhou ◽  
Qingli Li ◽  
Haichao Wang ◽  
Xiaobin Pang ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Active Immunotherapy ◽  
T Cell Epitopes ◽  
Neuroprotective Effects ◽  
Aβ Oligomers ◽  
Preclinical Ad ◽  
The Brain

Background: Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder, characterized by senile plaques and neurofibrillary tangles (NFTs). The amyloid-oligomer hypothesis indicates that the buildup of toxic oligomers in vivo is likely to impair memory and synaptic function. Methods: In our study, a kind of novel recombinant chimeric 12×(Aβ1-15-Th) antigen was developed as 12-mer Aβ1-42-like assembly vaccine. We designed this 12×(Aβ1-15-Th) antigen to mimic the assembly states of Aβ1-42 using twelve fold Aβ1–15 (B cell epitopes of human Aβ1-42) and foreign human T helper (Th) epitopes (as the T cell epitopes of Aβ1-42) constructs. Its immunogenicity as a subunit vaccine was tested on C57/BL6 mice, and the efficacy was shown by applying it to AD mice. Results: This 12×(Aβ1-15-Th) vaccine induced robust Aβ-specific antibodies in 3×Tg-AD and C57/BL6 mice. As early immunotherapeutic agent of AD, the 12×(Aβ1-15-Th) vaccine significantly improved the behavior performance of aged 3 × Tg-AD mice, and reduced the levels of soluble Aβ oligomers and soluble Aβ in the brain. In aged 3 × Tg-AD mice, immunotherapy with the 12×(Aβ1-15-Th) vaccine could prevent Aβ-induced decrease of synaptic proteins, which suggested that it has neuroprotective effects on the brain. Conclusion: The novel recombinant 12×(Aβ1-15-Th) chimeric vaccine targeting of pathological conformations of Aβ oligomers has shown obvious neuroprotective benefits in preclinical AD model mouse, which indicates it is a good candidate vaccine for the prophylaxis of AD.

scholarly journals Insulin differentially affects the distribution kinetics of amyloid beta 40 and 42 in plasma and brain

2017 ◽  
Vol 38 (5) ◽  
pp. 904-918 ◽  
Author(s):  
Suresh Kumar Swaminathan ◽  
Kristen M Ahlschwede ◽  
Vidur Sarma ◽  
Geoffry L Curran ◽  
Rajesh S Omtri ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Distribution Kinetics ◽  
In Vitro Bbb Model ◽  
First Time ◽  
Kinetics Of ◽  
The Brain ◽  
Distinct Distribution

Impaired brain clearance of amyloid-beta peptides (Aβ) 40 and 42 across the blood–brain barrier (BBB) is believed to be one of the pathways responsible for Alzheimer’s disease (AD) pathogenesis. Hyperinsulinemia prevalent in type II diabetes was shown to damage cerebral vasculature and increase Aβ accumulation in AD brain. However, there is no clarity on how aberrations in peripheral insulin levels affect Aβ accumulation in the brain. This study describes, for the first time, an intricate relation between plasma insulin and Aβ transport at the BBB. Upon peripheral insulin administration in wild-type mice: the plasma clearance of Aβ40 increased, but Aβ42 clearance reduced; the plasma-to-brain influx of Aβ40 increased, and that of Aβ42 reduced; and the clearance of intracerebrally injected Aβ40 decreased, whereas Aβ42 clearance increased. In hCMEC/D3 monolayers (in vitro BBB model) exposed to insulin, the luminal uptake and luminal-to-abluminal permeability of Aβ40 increased and that of Aβ42 reduced; the abluminal-to-luminal permeability of Aβ40 decreased, whereas Aβ42 permeability increased. Moreover, Aβ cellular trafficking machinery was altered. In summary, Aβ40 and Aβ42 demonstrated distinct distribution kinetics in plasma and brain compartments, and insulin differentially modulated their distribution. Cerebrovascular disease and metabolic disorders may disrupt this intricate homeostasis and aggravate AD pathology.

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 Fluorescent indolizine derivative YI-13 detects amyloid-β monomers, dimers, and plaques in the brain of 5XFAD Alzheimer transgenic mouse model

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243041
Author(s):  
DaWon Kim ◽  
Jeong Hwa Lee ◽  
Hye Yun Kim ◽  
Jisu Shin ◽  
Kyeonghwan Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Transgenic Mouse Model ◽  
Aβ Oligomers ◽  
Aβ Peptides ◽  
Soluble Aβ Oligomers ◽  
The Brain

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the aberrant production and accumulation of amyloid-β (Aβ) peptides in the brain. Accumulated Aβ in soluble oligomer and insoluble plaque forms are considered to be a pathological culprit and biomarker of the disorder. Here, we report a fluorescent universal Aβ-indicator YI-13, 5-(4-fluorobenzoyl)-7,8-dihydropyrrolo[1,2-b]isoquinolin-9(6H)-one, which detects Aβ monomers, dimers, and plaques. We synthesized a library of 26 fluorescence chemicals with the indolizine core and screen them through a series of in vitro tests utilizing Aβ as a target and YI-13 was selected as the final imaging candidate. YI-13 was found to stain and visualize insoluble Aβ plaques in the brain tissue, of a transgenic mouse model with five familial AD mutations (5XFAD), by a histochemical approach and to label soluble Aβ oligomers within brain lysates of the mouse model under a fluorescence plate reader. Among oligomers aggregated from monomers and synthetic dimers from chemically conjugated monomers, YI-13 preferred the dimeric Aβ.

scholarly journals Neuronal Models for Studying Tau Pathology

2010 ◽  
Vol 2010 ◽  
pp. 1-11
Author(s):  
Thorsten Koechling ◽  
Filip Lim ◽  
Felix Hernandez ◽  
Jesus Avila
Keyword(s):  
Tau Protein ◽  
Human Population ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Peptide ◽  
Tau Pathology ◽  
Histological Characteristics ◽  
The Brain ◽  
Phosphorylated Tau Protein ◽  
Genetically Modified Animals

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main pathological hallmarks in the brain: senile plaques containing -amyloid peptide and neurofibrillary tangles (NFTs), consisting of fibrillar polymers of abnormally phosphorylated tau protein. Both of these histological characteristics of the disease have been simulated in genetically modified animals, which today include numerous mouse, fish, worm, and fly models of AD. The objective of this review is to present some of the main animal models that exist for reproducing symptoms of the disorder and their advantages and shortcomings as suitable models of the pathological processes. Moreover, we will discuss the results and conclusions which have been drawn from the use of these models so far and their contribution to the development of therapeutic applications for AD.

scholarly journals Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?

2019 ◽  
Vol 20 (3) ◽  
pp. 558 ◽  
Author(s):  
Yuan Dong ◽  
Xiaoheng Li ◽  
Jinbo Cheng ◽  
Lin Hou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Tau Protein ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Cognitive Changes ◽  
Hyperphosphorylated Tau Protein ◽  
Common Causes ◽  
The Brain

Alzheimer’s disease (AD) is one of the most common causes of dementia. Its pathogenesis is characterized by the aggregation of the amyloid-β (Aβ) protein in senile plaques and the hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Current medications for AD can provide temporary help with the memory symptoms and other cognitive changes of patients, however, they are not able to stop or reverse the progression of AD. New medication discovery and the development of a cure for AD is urgently in need. In this review, we summarized drugs for AD treatments and their recent updates, and discussed the potential of microglia induced neuroinflammation as a target for anti-AD drug development.

scholarly journals Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1261
Author(s):  
Laura D’Andrea ◽  
Ramona Stringhi ◽  
Monica Di Luca ◽  
Elena Marcello
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Apoe Ε4 ◽  
Hyperphosphorylated Tau Protein ◽  
Ε4 Allele ◽  
Therapeutic Tools

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease.

scholarly journals The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 779
Author(s):  
Marzia Perluigi ◽  
Antonella Tramutola ◽  
Sara Pagnotta ◽  
Eugenio Barone ◽  
D. Allan Butterfield
Keyword(s):  
Down Syndrome ◽  
Senile Plaques ◽  
Redox Homeostasis ◽  
Antioxidant Defense System ◽  
Chromosome 21 ◽  
Potential Contribution ◽  
Physiological Relevance ◽  
Increased Risk ◽  
Hyperphosphorylated Tau Protein ◽  
The Brain

Down syndrome (DS) is the most common genetic cause of intellectual disability that is associated with an increased risk to develop early-onset Alzheimer-like dementia (AD). The brain neuropathological features include alteration of redox homeostasis, mitochondrial deficits, inflammation, accumulation of both amyloid beta-peptide oligomers and senile plaques, as well as aggregated hyperphosphorylated tau protein-containing neurofibrillary tangles, among others. It is worth mentioning that some of the triplicated genes encoded are likely to cause increased oxidative stress (OS) conditions that are also associated with reduced cellular responses. Published studies from our laboratories propose that increased oxidative damage occurs early in life in DS population and contributes to age-dependent neurodegeneration. This is the result of damaged, oxidized proteins that belong to degradative systems, antioxidant defense system, neuronal trafficking. and energy metabolism. This review focuses on a key element that regulates redox homeostasis, the transcription factor Nrf2, which is negatively regulated by BACH1, encoded on chromosome 21. The role of the Nrf2/BACH1 axis in DS is under investigation, and the effects of triplicated BACH1 on the transcriptional regulation of Nrf2 are still unknown. In this review, we discuss the physiological relevance of BACH1/Nrf2 signaling in the brain and how the dysfunction of this system affects the redox homeostasis in DS neurons and how this axis may contribute to the transition of DS into DS with AD neuropathology and dementia. Further, some of the evidence collected in AD regarding the potential contribution of BACH1 to neurodegeneration in DS are also discussed.

scholarly journals Increased MANF Expression in the Inferior Temporal Gyrus in Patients With Alzheimer Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Xue-Chun Liu ◽  
Xiu-Hong Qi ◽  
Hui Fang ◽  
Ke-Qing Zhou ◽  
Qing-Song Wang ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Er Stress ◽  
Senile Plaques ◽  
Control Group ◽  
Braak Stage ◽  
Early Stage Disease ◽  
Related Disorder ◽  
Inferior Temporal Gyrus ◽  
Immunofluorescence Labeling ◽  
The Brain

Alzheimer disease (AD) is an aging-related disorder linked to endoplasmic reticulum (ER) stress. The main pathologic feature of AD is the presence of extracellular senile plaques and intraneuronal neurofibrillary tangles (NFTs) in the brain. In neurodegenerative diseases, the unfolded protein response (UPR) induced by ER stress ensures cell survival. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against ER stress and has been implicated in the pathogenesis of AD. MANF is expressed in neurons of the brain and spinal cord. However, there have been no investigations on MANF expression in the brain of AD patients. This was addressed in the present study by immunohistochemistry, western blotting, and quantitative analyses of postmortem brain specimens. We examined the localization and expression levels of MANF in the inferior temporal gyrus of the cortex (ITGC) in AD patients (n = 5), preclinical (pre-)AD patients (n = 5), and age-matched non-dementia controls (n = 5) by double immunofluorescence labeling with antibodies against the neuron-specific nuclear protein neuronal nuclei (NeuN), ER chaperone protein 78-kDa glucose-regulated protein (GRP78), and MANF. The results showed that MANF was mainly expressed in neurons of the ITGC in all 3 groups; However, the number of MANF-positive neurons was significantly higher in pre-AD (Braak stage III/IV) and AD (Braak stage V/VI) patients than that in the control group. Thus, MANF is overexpressed in AD and pre-AD, suggesting that it can serve as a diagnostic marker for early stage disease.

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