scholarly journals Lipid microdomain modification sustains neuronal viability in models of Alzheimer’s disease

2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Silke Herzer ◽  
Sascha Meldner ◽  
Klara Rehder ◽  
Hermann-Josef Gröne ◽  
Viola Nordström
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Viability ◽  
Lipid Microdomain

scholarly journals Implication of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

2021 ◽  
Author(s):  
Qi Wu ◽  
Leonardo Cortez ◽  
Razieh Kamali-Jamil ◽  
Valerie Sim ◽  
Holger Wille ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Influence Function ◽  
Critical Role ◽  
Amyloid Β ◽  
Cholesterol Accumulation ◽  
Aβ Peptides ◽  
Neuronal Viability ◽  
Cultured Astrocytes ◽  
Aβ Production

Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aβ-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol level increases exosome secretion from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-CTFs, soluble APP, APP secretases and Aβ1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aβ production or by neutralizing exosomal Aβ peptide with an Aβ antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aβ peptides and influencing neuronal viability in the affected regions of the AD brain.

scholarly journals Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jong-Sung Park ◽  
Tae-In Kam ◽  
Saebom Lee ◽  
Hyejin Park ◽  
Yumin Oh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Critical Role ◽  
Subcutaneous Administration ◽  
Reactive Astrocytes ◽  
Reactive Astrocyte ◽  
Spatial Learning And Memory ◽  
Neuronal Viability ◽  
Age Related

AbstractAlzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R+ microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.

scholarly journals ALZHEIMER’S DISEASE: A CONSEQUENCE OF IMPAIRED MITOPHAGY?

2019 ◽  
pp. 75-80
Author(s):  
VIVEK SHARMA
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Proper Function ◽  
Neuronal Viability ◽  
Cellular Energy ◽  
Mitochondrial Homeostasis ◽  
Neuronal Homeostasis ◽  
Age Related ◽  
Characteristic Features

Neurodegenerative disorders involve complexities of the pathologies, characterized by the progressive loss of neuronal viability, leading to severe physical and cognitive impairments in affected patients. These disorders although may differ in clinical outcomes yet they share common features such as aggregation of neurotoxic metabolites and perturbed cellular and neuronal homeostasis. Mitochondrion is an indispensable organelle for neuronal survival, and its role and place have become critical in research arena of aging and neurodegenaration. The accumulation of damaged mitochondria has been linked to normal aging and multiple age-related disorders including Alzheimer’s disease (AD). Survival and proper function of mitochondria depend on several attributes that include mitochondrial biogenesis and fusion and fission. Mitophagy is an utmost requirement for degradation and removal of damaged mitochondria where the target mitochondria are identified by the autophagosomes and delivered to the lysosome for degradation. Mitophagy plays important roles in mitochondrial homeostasis, neuroprotection, and resistance to neurodegeneration. AD besides other characteristic features involves mitochondrial dysfunctional, bioenergetic deficit, and altered mitophagy. The autophagy/lysosome pathway that removes damaged mitochondria (mitophagy) is compromised in AD, resulting in the accumulation of dysfunctional mitochondria that contribute to synaptic dysfunction and cognitive deficits by triggering Aβ and Tau accumulation through increases in oxidative damage and cellular energy deficits. The present work reviews the various implications of mitophagy in relevance to the pathology of AD.

Tau alternative splicing in familial and sporadic tauopathies

2012 ◽  
Vol 40 (4) ◽  
pp. 677-680 ◽  
Author(s):  
Michael Niblock ◽  
Jean-Marc Gallo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alternative Splicing ◽  
Chromosome 17 ◽  
Binding Motif ◽  
Neuronal Viability ◽  
Protein Tau ◽  
Rna Analysis ◽  
Tau Isoforms ◽  
Exon 10

Six tau isoforms differing in their affinity for microtubules are produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene in adult human brain. Several MAPT mutations causing the familial tauopathy, FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17), affect alternative splicing of exon 10, encoding a microtubule-binding motif. Advanced RNA analysis methods have suggested that levels of exon 10-containing MAPT mRNA are elevated in Alzheimer's disease. Furthermore, the MAPT H1 haplotype, associated with Alzheimer's disease, promotes exon 10 inclusion in MAPT mRNA. Thus an accurate regulation of tau alternative splicing is critical for the maintenance of neuronal viability, and its alteration might be a contributing factor to Alzheimer's disease. Tau alternative splicing could represent a target for therapeutic intervention to delay the progression of pathology in familial as well as sporadic tauopathies.

scholarly journals Alzheimer’s disease as a metabolic disorder

OCL ◽  
2018 ◽  
Vol 25 (4) ◽  
pp. D403 ◽  
Author(s):  
George S. Bloom ◽  
Andrés Norambuena
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
Amyloid Β ◽  
Direct Consequence ◽  
Building Blocks ◽  
Neuronal Function ◽  
Aβ Peptides ◽  
Neuronal Viability ◽  
Poorly Soluble

Alzheimer’s disease (AD) is defined by memory loss and cognitive impairment, along with the accumulation in brain of two types of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Both plaques and tangles are composed predominantly of poorly soluble filaments that respectively assemble from amyloid-β (Aβ) peptides and the neuron-specific, microtubule-associated protein, tau. It is now widely acknowledged that soluble oligomers of Aβ and tau, the building blocks of plaques and tangles, are principal drivers of AD pathogenesis by acting coordinately to impair and destroy synapses, and kill neurons. The behavioral features of AD are a direct consequence of these attacks on synapses and neuronal viability, which in turn reflect a reduced capacity of AD neurons to utilize energy sources needed to maintain neuronal function and vitality. In other words, AD neurons are starving, even when they may be surrounded by abundant nutrients. Here, we review some of the evidence for the metabolic deficiencies of neurons in AD and how they impact neuronal health.

scholarly journals Alzheimer's Disease: Another Target for Heparin Therapy

2009 ◽  
Vol 9 ◽  
pp. 891-908 ◽  
Author(s):  
Luigi Bergamaschini ◽  
Emanuela Rossi ◽  
Carlo Vergani ◽  
Maria Grazia De Simoni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Elderly ◽  
Heparin Therapy ◽  
Therapeutic Interventions ◽  
Neuronal Viability ◽  
Β Protein ◽  
Tissue Changes

Alzheimer's disease (AD) is the leading cause of dementia and cognitive decline in the elderly. Brain tissue changes indicate that the two main proteins involved in AD are amyloid-β(A-β), which is associated with the formation of senile amyloid plaques, and tau, which is associated with the formation of neurofibrillary tangles. Although a central role for A-β in the pathogenesis of AD is indisputable, considerable evidence indicates that A-β production is not the sole culprit in AD pathology. AD is also accompanied by an inflammatory response that contributes to irreversible changes in neuronal viability and brain function, and accumulating evidence supports the pivotal role of complement and contact systems in its pathogenesis and progression. The complexity of AD pathology provides numerous potential targets for therapeutic interventions. Compounds that interact directly with A-β protein or interfere with its production and/or aggregation can reduce the inflammatory and neurotoxic effects of A-β, and heparin, a glycosaminoglycan mixture currently used in the prophylaxis and treatment of thrombosis, might be a candidate, as recent research has been extended to consider its nonanticoagulant properties, including its modulation of various proteases and anti-inflammatory activity.

Cognitive control constrains memory attributions

2019 ◽  
Vol 42 ◽  
Author(s):  
Colleen M. Kelley ◽  
Larry L. Jacoby
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Control

Abstract Cognitive control constrains retrieval processing and so restricts what comes to mind as input to the attribution system. We review evidence that older adults, patients with Alzheimer's disease, and people with traumatic brain injury exert less cognitive control during retrieval, and so are susceptible to memory misattributions in the form of dramatic levels of false remembering.

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