Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer's disease

2012 ◽  
Vol 33 (7) ◽  
pp. 1329-1342 ◽  
Author(s):  
Maria Teresa Ferretti ◽  
Martin A. Bruno ◽  
Adriana Ducatenzeiler ◽  
William L. Klein ◽  
A. Claudio Cuello
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Aβ Oligomers ◽  
Model Of Alzheimer’S Disease

scholarly journals CNI-1493 inhibits Aβ production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

2008 ◽  
Vol 205 (7) ◽  
pp. 1593-1599 ◽  
Author(s):  
Michael Bacher ◽  
Richard Dodel ◽  
Bayan Aljabari ◽  
Kathy Keyvani ◽  
Philippe Marambaud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Performance ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
App Processing ◽  
Model Of Alzheimer’S Disease

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid β protein (Aβ) peptide “oligomers” and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Aβ assembly and protects neuronal cells from the toxic effect of soluble Aβ oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Aβ deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Aβ accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.

scholarly journals Glucose facilitates Aβ oligomerization and tau phosphorylation in C. elegans model of Alzheimer’s disease

2017 ◽  
Author(s):  
Waqar Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Metabolism ◽  
Disease Progression ◽  
Neurofibrillary Tangles ◽  
Tau Phosphorylation ◽  
Egg Laying ◽  
Aβ Oligomers ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

AbstractFormation of Aβ plaques from peptide oligomers and development of neurofibrillary tangles from hyperphosphorylated tau are hallmarks of Alzheimer’s disease (AD). These markers of AD severity are further associated with impaired glucose metabolism. However, the exact role of glucose metabolism on disease progression has not been elucidated. In this study, the effects of glucose on Aβ and tau-mediated toxicity are investigated using a C. elegans model system. We find that addition of glucose or 2-deoxy-d-glucose (2DOG) to the growth medium delayed Aβ-associated paralysis, though it was unable to restore previously impaired acetylcholine neurotransmission in pre-existing Aβ-mediated pathology. Glucose also inhibited egg laying and hatching in the worms that express Aβ. The harmful effects of glucose were associated with an increase in toxic Aβ oligomers. Increased phosphorylation of tau is associated with formation of neurofibrillary tangles (NFTs) and increased severity of AD, but O-β-GlcNAcylation can inhibit phosphorylation of adjacent phosphorylation sites. We reasoned that high glucose levels might induce tau O-β-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectation, glucose increased tau phosphorylation but not O-β-GlcNAcylation. Increasing O-β-GlcNAcylation, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene does interfere with and therefore reduce tau phosphorylation. Furthermore, reducing O-β-GlcNAcylation by suppressing O-GlcNAc transferase (ogt-1) gene causes an increase in tau phosphorylation. These results suggest that protective O-β-GlcNAcylation is not induced by glucose. Instead, as with vertebrates, we demonstrate that high levels of glucose exacerbate disease progression by promoting Aβ aggregation and tau hyperphosphorylation, resulting in disease symptoms of increased severity. The effects of glucose cannot be effectively managed by manipulating O-β-GlcNAcylation in the tau models of AD in C. elegans. Our observations suggest that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression.

scholarly journals Energy-dependent transport at dural lymphatic vessels is necessary for Aβ brain clearance in Alzheimer’s disease

2019 ◽  
Author(s):  
Liudmila Romanova ◽  
Heidi Phillips ◽  
Gregory S. Calip ◽  
Kyle Hauser ◽  
Daniel A. Peterson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Lymphatic Vessels ◽  
Normal Brain ◽  
Aβ Oligomers ◽  
Cytoplasmic Inclusions ◽  
Model Of Alzheimer’S Disease ◽  
Dependent Transport ◽  
Energy Dependent

AbstractViewed as an imbalance between production and clearance of toxic Aβ peptides, Alzheimer’s disease is a candidate for therapies to augment brain waste removal. Prior work has shown that Aβ accumulates in meninges with aging as a byproduct of normal brain activity, in parallel with build-up of Aβ oligomers in neurons, blood vessels, and interstitial fluid. Using the TgF344-AD rat model of Alzheimer’s disease, we now report that dural lymphatic vessels specifically accumulate neurotoxic pyroglutamate amyloid beta (pE3-Aβ) with aging. Notably, accelerated amyloidosis is observed in meninges after ligation of cervical lymphatics, together with significantly increased pE3-Aβ and Aβ42 deposition in upstream brain regions implicated in Alzheimer’s disease. Blockade of lymphatic clearance is not sufficiently compensated by other efflux pathways, suggesting a necessary role of Aβ clearance at the level of lymphatics. We further report that dural lymphatic cells actively clear Aβ via energy-dependent mechanisms, and lymphatic Aβ transport is significantly impaired both in normal aging and in Alzheimer’s disease. Dural lymphatic cells isolated from the TgF344-AD rat show ultrastructural abnormalities in mitochondria and abnormal cytoplasmic inclusions, with a distinct transcriptional profile implicating failure of energy-dependent transport. Finally, using human meninges treated with FocusDeep tissue clearing, we demonstrate using whole mount panoramic imaging that dural lymphatic vessels comprise a structurally diverse intracranial vascular network that accumulates pE3-Aβ with aging, similar to the rat model. We conclude that intracranial meningeal and extracranial cervical lymphatic vessels are targets for Alzheimer’s disease therapies focused on improving amyloid clearance.One Sentence SummaryLymphatic vessels remove Aβ from the brain via energy-dependent active transport mechanisms, and blockage of extracranial lymphatic drainage is sufficient to cause significant acceleration of intracranial Alzheimer’s Aβ pathology in both meninges and brain.

scholarly journals Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer’s Disease

2020 ◽  
Vol 21 (19) ◽  
pp. 7337
Author(s):  
Tom L. Broderick ◽  
Suhail Rasool ◽  
Rongzi Li ◽  
Yuxian Zhang ◽  
Miranda Anderson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Exercise Training ◽  
Mouse Model ◽  
Synaptic Function ◽  
Neuroprotective Effects ◽  
Aβ Oligomers ◽  
Markers Of Inflammation ◽  
Model Of Alzheimer’S Disease ◽  
Ad Mouse Model

To date, there is no cure or effective treatment for Alzheimer’s disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aβ) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aβ and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aβ oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aβ oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

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