scholarly journals URMC-099 Prophylaxis Repairs Hippocampal Vascular Damage in an Orthopedic Model of Delirium Superimposed on Dementia

2021 ◽  
Author(s):  
Patrick Miller-Rhodes ◽  
Herman Li ◽  
Ravikanth Velagapudi ◽  
Niccolo Terrando ◽  
Harris A Gelbard
Keyword(s):  
Cognitive Deficits ◽  
Microglial Activation ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Endothelial Activation ◽  
Surgical Trauma ◽  
Data Link ◽  
Synapse Loss ◽  
The Brain ◽  
Delirium Superimposed On Dementia

Systemic perturbations can drive a neuroimmune cascade after surgical trauma, including affecting the blood-brain barrier (BBB), activating microglia, and contributing to cognitive deficits such as delirium. Delirium superimposed on dementia (DSD) is a particularly debilitating complication that renders the brain further vulnerable to neuroinflammation and neurodegeneration, albeit these molecular mechanisms remain poorly understood. Here we have used an orthopedic model of tibial fracture/fixation in APPSwDI/mNos2-/- AD (CVN-AD) mice to investigate relevant pathogenetic mechanisms underlying DSD. We conducted the present study in 6 months-old CVN-AD mice, an age at which we speculated amyloid-β pathology had not saturated BBB and neuroimmune functioning. We found that URMC-099, our brain-penetrant anti-inflammatory neuroprotective drug, prevented inflammatory endothelial activation, synapse loss, and microglial activation in our DSD model. Taken together, our data link post-surgical endothelial activation, microglial MafB immunoreactivity, and synapse loss as key substrates for DSD, all of which can be reversed by URMC-099.

scholarly journals Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

2020 ◽  
Vol 14 ◽  
Author(s):  
Katiuscia Pagano ◽  
Simona Tomaselli ◽  
Henriette Molinari ◽  
Laura Ragona
Keyword(s):  
Molecular Weight ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Natural Compounds ◽  
Preventive Therapy ◽  
Small Subset ◽  
Aβ Peptide ◽  
Aβ Oligomers ◽  
Chemical Structures ◽  
The Brain

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-β (Aβ) peptides are recognized as the main cause of AD progression, leading to the formation of toxic Aβ oligomers and to the deposition of β-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with Aβ aggregation by direct interaction with Aβ peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the Aβ regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and β1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

Modifiable Risk Factors Associated with Alzheimer’s Disease with Special Reference to Sleep Disturbance

2021 ◽  
Vol 20 ◽  
Author(s):  
Pallavi Singh Chauhan ◽  
Meerambika Mishra ◽  
Bhupendra Koul ◽  
Mayank Sharma ◽  
Dhananjay Yadav
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Contributing Factors ◽  
Obstructive Sleep ◽  
Rhythm Disorder ◽  
Impaired Sleep ◽  
Nighttime Sleep

: Sleep disorders has been shown to increase the risk of dementia. This particular aspect may affect the cognition of the patient, leading to behavioral disorders, and depression. In early symptomatic Alzheimer’s disease (AD), default mode network (DMN) disruption occurs and progresses along with the course of the disease. This review mainly focuses on the leading causes of AD along with management of conditions like insomnia, obstructive sleep apnea, nighttime sleep duration, circadian rhythm disorder (CRD), neuroendocrine alternation and impaired sleep to prevent the use of drugs that can cause complications, especially falls or additional cognitive deficits. Moreover, this study highlights identification of molecular mechanisms like effect of impaired sleep on amyloid β (Aβ) and Tau dynamics, impaired proteostasis along with appropriate measures to treat few contributing factors lead to insomnia in AD or mild cognitive impairment (MCI).

scholarly journals β-site specific intrabodies to decrease and prevent generation of Alzheimer's Aβ peptide

2005 ◽  
Vol 168 (6) ◽  
pp. 863-868 ◽  
Author(s):  
Paolo Paganetti ◽  
Verena Calanca ◽  
Carmela Galli ◽  
Muriel Stefani ◽  
Maurizio Molinari
Keyword(s):  
Cleavage Site ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Single Chain ◽  
Cellular Events ◽  
Novel Approach ◽  
Er Retention ◽  
Intracellular Expression ◽  
The Brain

Endoproteolysis of the β-amyloid precursor protein (APP) by β- and γ-secretases generates the toxic amyloid β-peptide (Aβ), which accumulates in the brain of Alzheimer's disease (AD) patients. Here, we established a novel approach to regulate production of Aβ based on intracellular expression of single chain antibodies (intrabodies) raised to an epitope adjacent to the β-secretase cleavage site of human APP. The intrabodies rapidly associated, within the endoplasmic reticulum (ER), with newly synthesized APP. One intrabody remained associated during APP transport along the secretory line, shielded the β-secretase cleavage site and facilitated the alternative, innocuous cleavage operated by α-secretase. Another killer intrabody with an ER retention sequence triggered APP disposal from the ER. The first intrabody drastically inhibited and the second almost abolished generation of Aβ. Intrabodies association with specific substrates rather than with enzymes, may modulate intracellular processes linked to disease with highest specificity and may become instrumental to investigate molecular mechanisms of cellular events.

Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior

2020 ◽  
Vol 78 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Wei Wang ◽  
Cuibai Wei ◽  
Meina Quan ◽  
Tingting Li ◽  
Jianping Jia
Keyword(s):  
Oxidative Stress ◽  
Memory Impairment ◽  
Molecular Mechanisms ◽  
Psychological Symptoms ◽  
Amyloid Β ◽  
Serotonergic System ◽  
Inflammatory Factors ◽  
The Relationship ◽  
The Brain ◽  
And Oxidative Stress

Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia.

scholarly journals Effects of Amyloid Beta Peptide on Neurovascular Cells

2013 ◽  
Vol 1 (1) ◽  
Author(s):  
Sholpan Askarova ◽  
Andrey Tsoy ◽  
Tamara Shalakhmetova ◽  
James C-M Lee
Keyword(s):  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Amyloid Β Peptide ◽  
Inflammatory Reactions ◽  
Inflammatory Processes ◽  
The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder, which is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in specific regions of the brain, accompanied by impairment of the neurons, and progressive deterioration of cognition and memory of affected individuals. Although the cause and progression of AD are still not well understood, the amyloid hypothesis is dominant and widely accepted. According to this hypothesis, an increased deposition of amyloid-β peptide (Aβ) in the brain is the main cause of the AD’s onset and progression. There is increasing body of evidence that blood-brain barrier (BBB) dysfunction plays an important role in the development of AD, and may even precede neuron degeneration in AD brain. In the early stage of AD, microvasculature deficiencies, inflammatory reactions, surrounding the cerebral vasculature and endothelial dysfunctions are commonly observed. Continuous neurovascular degeneration and accumulation of Aβ on blood vessels resulting in cerebral amyloid angiopathy is associated with further progression of the disease and cognitive decline. However, little is known about molecular mechanisms that underlie Aβ induced damage of neurovascular cells. In this regards, this review is aimed to address how Aβ impacts the cerebral endothelium.  Understanding the cellular pathways triggered by Aβ leading to alterations in cerebral endothelial cells structure and functions would provide insights into the mechanism of BBB dysfunction and inflammatory processes in Alzheimer’s, and may offer new approaches for prevention and treatment strategies for AD. 

scholarly journals Low-grade peripheral inflammation affects brain pathology in the AppNL-G-Fmouse model of Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Junhua Xie ◽  
Nina Gorlé ◽  
Charysse Vandendriessche ◽  
Griet Van Imschoot ◽  
Elien Van Wonterghem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Immune Cell ◽  
Amyloid Β ◽  
Peripheral Inflammation ◽  
Low Grade ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

AbstractAlzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid β (Aβ) and neurofibrillary tangles. The last decade, it became increasingly clear that neuroinflammation plays a key role in both the initiation and progression of AD. Moreover, also the presence of peripheral inflammation has been extensively documented. However, it is still ambiguous whether this observed inflammation is cause or consequence of AD pathogenesis. Recently, this has been studied using amyloid precursor protein (APP) overexpression mouse models of AD. However, the findings might be confounded by APP-overexpression artifacts. Here, we investigated the effect of low-grade peripheral inflammation in the APP knock-in (AppNL-G-F) mouse model. This revealed that low-grade peripheral inflammation affects (1) microglia characteristics, (2) blood-cerebrospinal fluid barrier integrity, (3) peripheral immune cell infiltration and (4) Aβ deposition in the brain. Next, we identified mechanisms that might cause this effect on AD pathology, more precisely Aβ efflux, persistent microglial activation and insufficient Aβ clearance, neuronal dysfunction and promotion of Aβ aggregation. Our results further strengthen the believe that even low-grade peripheral inflammation has detrimental effects on AD progression and may further reinforce the idea to modulate peripheral inflammation as a therapeutic strategy for AD.

scholarly journals Treatment with Bifidobacteria can suppress Aβ accumulation and neuroinflammation in APP/PS1 mice

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10262
Author(s):  
Qiong Wu ◽  
Qifa Li ◽  
Xuan Zhang ◽  
Michael Ntim ◽  
Xuefei Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Amyloid Β ◽  
The Elderly ◽  
Inflammatory Factors ◽  
Complex Disorder ◽  
Tnf Α ◽  
The Brain ◽  
Excessive Accumulation

Background Alzheimer’s disease (AD), being a complex disorder, is affected either by genetic or environmental factors or both. It is observed that there is an excessive accumulation of amyloid β (Aβ) in the extracellular space of the brain. AD is the first neurodegenerative disease in the elderly, and so far there is no effective treatment. In recent years, many studies have reported that Alzheimer’s disease has a relationship with gut microflora, indicating that regulating gut microbiota could offer therapeutic intervention for AD. This study explored the effect Bifidobacteria has in averting AD. Methods WT and APP/PS1 mice were used for the experiments. The mice were randomly assigned to four groups: WT group, WT + Bi group, AD group (APP/PS1 mouse) and AD + Bi group (Bifidobacteria-treated APP/PS1 mouse). Treatment with Bifidobacteria lasted for 6 months and mice were prepared for immunohistochemistry, immunofluorescence, Thioflavin S staining, Western blotting, PCR and Elisa quantitative assay. Results The results show that after 6 months of treatment with Bifidobacteria signiis to be lesficantly reduces Aβ deposition in cortex and hippocampus of AD mice. The level of insoluble Aβ in the hippocampus and cortex of AD+Bi mice was decreased compared with AD mice. Meanwhile, a significant decrease in the level of soluble Aβ in the cortex of AD+Bi mice but not in the hippocampus was observed. The activation of microglia and the release of inflammatory factors were also determined in this study. From the results, Bifidobacteria inhibited microglial activation and reduced IL-1β, TNF-α, IL-4, IL-6 and INF-γ release. Altogether, these results implied that Bifidobacteria can alleviate the pathological changes of AD through various effects.

scholarly journals Alzheimer′s brain inoculation in Aβ-plaque bearing mice: synaptic loss is linked to tau seeding and low microglial activity

2021 ◽  
Author(s):  
Suzanne Lam ◽  
Susana Boluda ◽  
Anne Sophie Herard ◽  
Fanny Petit ◽  
Sabiha Eddarkaoui ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Genetic Manipulation ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
Intracerebral Injection ◽  
Neuritic Plaques ◽  
Synaptic Loss ◽  
Brain Extracts ◽  
Amyloid Load ◽  
The Brain

Alzheimer's disease (AD) is characterized by synaptic alterations that lead to cognitive impairments and by a number of lesions including extracellular amyloid–β (Aβ) plaques, intracellular tau accumulation and neuroinflammation. The contribution of these lesions to synaptic alterations is still debated. Through the intracerebral injection of human AD brain extracts into an Aβ plaque–bearing mouse model that does not overexpress tau we recapitulated all these AD lesions. In particular neuritic plaques, AD-like neurofibrillary tangles and neuropil threads, that spread through the brain, were identified and characterized. Interestingly neuritic plaques but not other tau-positive lesions were observed in control-inoculated animals as well as in non-inoculated amyloid-bearing mice, suggesting that these lesions do not require exogeneous tau to be initiated. Inoculation of different human AD brain extracts to mice led to lesional heterogeneity and to enhanced synaptic loss and cognitive impairments. Relationships between synaptic alterations or cognitive impairments and AD pathology were evaluated by exploiting the induced lesional heterogeneity. Synaptic loss and cognitive deficits were associated with the severity of tau lesions and to lower microglial load, but not to amyloid load. Our results outline that new mouse models of AD bearing both Aβ plaques and tau lesions, and based on AD brain extracts inoculation, allow to investigate AD neurodegenerative processes. They highlight the contribution of tau to synaptic impairments in a model that does not rely on genetic manipulation of tau protein and indicate that microglial activity may protect against synaptic loss.

scholarly journals Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Junjun Ni ◽  
Zhou Wu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Neuronal Dysfunction ◽  
Pathological Feature ◽  
Negative Effects ◽  
Inflammatory Disorders ◽  
Peripheral Immune Cells ◽  
The Brain

As a physiological response to injury in the internal body organs, inflammation is responsible for removing dangerous stimuli and initiating healing. However, persistent and exaggerative chronic inflammation causes undesirable negative effects in the organs. Inflammation occurring in the brain and spinal cord is known as neuroinflammation, with microglia acting as the central cellular player. There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer’s disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs. In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, “dampening inflammation” through the inhibition of cathepsin (Cat)B or CatS may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD.

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