scholarly journals Antioxidant Therapies for Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Ye Feng ◽  
Xiaochuan Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Toxic Substances ◽  
Synaptic Loss ◽  
Recent Developments ◽  
Multiple Cell ◽  
Future Potential ◽  
And Behavior

Alzheimer’s disease (AD) is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behavior and ultimately leads to death. The histopathological changes of Alzheimer’s disease include neuronal and synaptic loss, formation of extracellular senile plaques and intracellular neurofibrillary tangles in brain. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer’s disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer’s disease. Many years of studies show that antioxidant therapies have enjoyed general success in preclinical studies. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for Alzheimer’s disease and thus provides indications for future potential antioxidant therapeutic strategies of neurodegenerative diseases.

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 Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer’s disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shan-Shan Wang ◽  
Zi-Kai Liu ◽  
Jing-Jing Liu ◽  
Qing Cheng ◽  
Yan-Xia Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Disease Stage ◽  
Assay Method ◽  
Imaging Probe ◽  
Asparaginyl Endopeptidase ◽  
Potential Biomarker ◽  
The Brain

Abstract Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

scholarly journals Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

2021 ◽  
Vol 23 (1) ◽  
pp. 345
Author(s):  
Yaping Liu ◽  
Runrong Ding ◽  
Ze Xu ◽  
Yuan Xue ◽  
Dongdong Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Control System ◽  
Protein Quality ◽  
Early Stage ◽  
Senile Plaques ◽  
Protein Quality Control ◽  
Quality Control System ◽  
Protein Quality Control System

Alzheimer’s disease (AD) is characterized by the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs), as well as neuronal dysfunctions in the brain, but in fact, patients have shown a sustained disease progression for at least 10 to 15 years before these pathologic biomarkers can be detected. Consequently, as the most common chronic neurological disease in the elderly, the challenge of AD treatment is that it is short of effective biomarkers for early diagnosis. The protein quality control system is a collection of cellular pathways that can recognize damaged proteins and thereby modulate their turnover. Abundant evidence indicates that the accumulation of abnormal proteins in AD is closely related to the dysfunction of the protein quality control system. In particular, it is the synthesis, degradation, and removal of essential biological components that have already changed in the early stage of AD, which further encourages us to pay more attention to the protein quality control system. The review mainly focuses on the endoplasmic reticulum system (ERS), autophagy–lysosome system (ALS) and the ubiquitin–proteasome system (UPS), and deeply discusses the relationship between the protein quality control system and the abnormal proteins of AD, which can not only help us to understand how and why the complex regulatory system becomes malfunctional during AD progression, but also provide more novel therapeutic strategies to prevent the development of AD.

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 Calpain Dysregulation in Alzheimer’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Adriana Ferreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Marked Decrease ◽  
Senile Plaques ◽  
Cysteine Proteases ◽  
Axonal Guidance ◽  
Cell Functions ◽  
Multiple Cell ◽  
Axonal Guidance Growth ◽  
Differentiation And Proliferation

Alzheimer’s disease (AD) is characterized by the presence of senile plaques and neurofibrillary tangles in the neocortex and hippocampus of AD patients. In addition, a marked decrease in synaptic contacts has been detected in these affected brain areas. Due to its prevalence in the aging population, this disease has been the focus of numerous studies. The data obtained from those studies suggest that the mechanisms leading to the formation of the hallmark lesions of AD might be linked. One of such mechanisms seems to be the dysregulation of calcium homeostasis that results in the abnormal activation of calpains. Calpains are a family of Ca2+-dependent cysteine proteases that play a key role in multiple cell functions including cell development, differentiation and proliferation, axonal guidance, growth cone motility, and cell death, among others. In this paper, we briefly reviewed data on the structure of these proteases and their regulation under normal conditions. We also summarized data underscoring the participation of calpains in the neurodegenerative mechanisms associated with AD.

Tacrine-Natural-Product Hybrids for Alzheimer’s Disease Therapy

2020 ◽  
Vol 27 (26) ◽  
pp. 4392-4400 ◽  
Author(s):  
María Jesús Oset-Gasque ◽  
José Luis Marco-Contelles
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Complex Nature ◽  
Biological Targets ◽  
Disease Therapy ◽  
Aβ Aggregation ◽  
Recent Developments ◽  
New Compounds ◽  
Ad Therapy

Alzheimer’s disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation, Aβ-aggregation resulting in senile plaques formation, and hyperphosphorylation of tau-protein leading to neurofibrillary tangles. Due to its multifactorial and complex nature, multitarget directed small-molecules able to simultaneously inhibit or bind diverse biological targets involved in the progress and development of AD are considered now the best therapeutic strategy to design new compounds for AD therapy. Among them, tacrine is a very well known standard-gold ligand, and natural products have been a traditional source of new agents for diverse therapeutic treatments. In this review, we will update recent developments of multitarget tacrinenatural products hybrids for AD therapy.

scholarly journals Aminopeptidase A contributes to biochemical, anatomical and cognitive defects in Alzheimer’s disease (AD) mouse model and is increased at early stage in sporadic AD brain

2021 ◽  
Author(s):  
Audrey Valverde ◽  
Julie Dunys ◽  
Thomas Lorivel ◽  
Delphine Debayle ◽  
Anne-Sophie Gay ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Glutaminyl Cyclase ◽  
Aβ Aggregation ◽  
Key Enzyme ◽  
Aminopeptidase A ◽  
Main Components ◽  
Cognitive Defects

AbstractOne of the main components of senile plaques in Alzheimer’s disease (AD)-affected brain is the Aβ peptide species harboring a pyroglutamate at position three pE3-Aβ. Several studies indicated that pE3-Aβ is toxic, prone to aggregation and serves as a seed of Aβ aggregation. The cyclisation of the glutamate residue is produced by glutaminyl cyclase, the pharmacological and genetic reductions of which significantly alleviate AD-related anatomical lesions and cognitive defects in mice models. The cyclisation of the glutamate in position 3 requires prior removal of the Aβ N-terminal aspartyl residue to allow subsequent biotransformation. The enzyme responsible for this rate-limiting catalytic step and its relevance as a putative trigger of AD pathology remained yet to be established. Here, we identify aminopeptidase A as the main exopeptidase involved in the N-terminal truncation of Aβ and document its key contribution to AD-related anatomical and behavioral defects. First, we show by mass spectrometry that human recombinant aminopeptidase A (APA) truncates synthetic Aβ1-40 to yield Aβ2-40. We demonstrate that the pharmacological blockade of APA with its selective inhibitor RB150 restores the density of mature spines and significantly reduced filopodia-like processes in hippocampal organotypic slices cultures virally transduced with the Swedish mutated Aβ-precursor protein (βAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Aβ- and Aβ1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA inhibitors and shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of pE3-42Aβ-positive plaques, APA activity is augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA is a key enzyme involved in Aβ N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.

scholarly journals OXIDATIVE STRESS IN ALZHEIMER’S DISEASE–EVALUATING THE AMYLOID BETA HYPOTHESIS

2021 ◽  
pp. 32-38
Author(s):  
SWETHA G. ◽  
ANJALI RAJ ◽  
SANIYA TABASSUM ◽  
DOUGLAS ZORINMAWIA CHHAKCHHUAK
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Senile Plaques ◽  
Redox Balance ◽  
Tau Proteins ◽  
Significant Component ◽  
And Behavior ◽  
The Relationship

Dementia is defined by the debilitation of cognition and behavior of individuals more than 65 y. Alzheimer's disease (AD) is the most pervasive pervasive form of dementia, afflicting around 47 million individuals worldwide. Oxidative damage is a significant component in the pathophysiology of Alzheimer's disease (AD). Assessment of Alzheimer's disease mind has shown a lot of oxidative harm, related with both trademark pathologies (senile plaques and neurofibrillary tangles) just as in typical seeming pyramidal neurons. By the by, the process that eventually causes disruption of redox balance and furthermore the origin of the free radicals are as yet hazy. There is likewise the accessibility of proof that oxidative stress may enhance the conglomeration and production of Aβ and furthermore help the polymerization just as phosphorylation of tau, subsequently making a pernicious cycle that invigorates the development and even commencement of Alzheimer's. These neurotic trademarks have complex proportional collaborations with cholinergic abrasions. This review may give complemental data for understanding the relationship between oxidative stress, amyloid plaques, tau proteins and cholinergic system in processing of AD.

scholarly journals Neuropathology of Aging in Cats and its Similarities to Human Alzheimer’s Disease

2021 ◽  
Vol 2 ◽  
Author(s):  
Lorena Sordo ◽  
Alessandra C. Martini ◽  
E. Fiona Houston ◽  
Elizabeth Head ◽  
Danièlle Gunn-Moore
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Brain Regions ◽  
Hyperphosphorylated Tau ◽  
Age Related ◽  
Cat Brain ◽  
Amyloid Aβ ◽  
Intraneuronal Aβ

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling.

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