scholarly journals Synaptic loss and retention of different classic cadherins with LTP-associated synaptic structural remodeling in vivo

Hippocampus ◽  
2010 ◽  
Vol 22 (1) ◽  
pp. 17-28 ◽  
Author(s):  
George W. Huntley ◽  
Alice M. Elste ◽  
Shekhar B. Patil ◽  
Ozlem Bozdagi ◽  
Deanna L. Benson ◽  
...  
Keyword(s):  
Synaptic Loss ◽  
Structural Remodeling

scholarly journals Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

2019 ◽  
Author(s):  
Annie Lee ◽  
Chandana Kondapalli ◽  
Daniel M. Virga ◽  
Tommy L. Lewis ◽  
So Yeon Koo ◽  
...  
Keyword(s):  
Genome Engineering ◽  
Pyramidal Neurons ◽  
Es Cells ◽  
Mitochondrial Fission ◽  
Significant Loss ◽  
Synaptic Loss ◽  
Structural Remodeling ◽  
Swedish Mutation ◽  
Human Neurons

AbstractDuring the early stages of Alzheimer’s disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble Aβ plaques. We observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites in the hAPPSWE,IND transgenic AD mouse model (J20), corresponding to the dendritic domain receiving presynaptic inputs from the entorhinal cortex and where the earliest synaptic loss is detected in vivo. We also observed significant loss of mitochondrial biomass in human neurons derived from a new model of human ES cells where CRISPR-Cas9-mediated genome engineering was used to introduce the ‘Swedish’ mutation bi-allelically (APPSWE/SWE). Recent work uncovered that Aβ42o mediates synaptic loss by over-activating the CAMKK2-AMPK kinase dyad, and that AMPK is a central regulator of mitochondria homeostasis in non-neuronal cells. Here, we demonstrate that Aβ42o-dependent over-activation of CAMKK2-AMPK mediates synaptic loss through coordinated MFF-dependent mitochondrial fission and ULK2-dependent mitophagy in dendrites of PNs. We also found that the ability of Aβ42o-dependent mitochondrial remodeling to trigger synaptic loss requires the ability of AMPK to phosphorylate Tau on Serine 262. Our results uncover a unifying stress-response pathway triggered by Aβo and causally linking structural remodeling of dendritic mitochondria to synaptic loss.

scholarly journals In vivo imaging of synaptic loss in Alzheimer’s disease with [18F]UCB-H positron emission tomography

2019 ◽  
Vol 47 (2) ◽  
pp. 390-402 ◽  
Author(s):  
Christine Bastin ◽  
Mohamed Ali Bahri ◽  
François Meyer ◽  
Marine Manard ◽  
Emma Delhaye ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
In Vivo Imaging ◽  
Emission Tomography ◽  
Synaptic Loss ◽  
Positron Emission

scholarly journals 3D Mapping of Neurofibrillary Tangle Burden in the Human Medial Temporal Lobe

2021 ◽  
Author(s):  
Paul A Yushkevich ◽  
Mónica Muñoz López ◽  
Maria Mercedes Iñiguez de Onzoño Martin ◽  
Ranjit Ittyerah ◽  
Sydney Lim ◽  
...  
Keyword(s):  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Ex Vivo ◽  
Neurofibrillary Tangle ◽  
Imaging Biomarkers ◽  
Synaptic Loss ◽  
The Brain ◽  
Transentorhinal Region ◽  
Anterior Posterior

Abstract Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.

scholarly journals In vivo measurement of widespread synaptic loss and associated tau accumulation in early Alzheimer’s disease

2020 ◽  
Vol 16 (S4) ◽  
Author(s):  
Adam P. Mecca ◽  
Ryan S. O'Dell ◽  
Ming‐Kai Chen ◽  
Mika Naganawa ◽  
Takuya Toyonaga ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Loss ◽  
In Vivo Measurement ◽  
Early Alzheimer’S Disease

scholarly journals Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Barbara Tate ◽  
Timothy D. McKee ◽  
Robyn M. B. Loureiro ◽  
Jo Ann Dumin ◽  
Weiming Xia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gamma Secretase ◽  
Synaptic Loss ◽  
App Processing ◽  
Protein Substrates ◽  
Secretase Activity ◽  
Small Molecule Modulators ◽  
Multiple Chemical

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by Aβpeptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Sinceγ-secretase is critical for Aβproduction, many in the biopharmaceutical community focused onγ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to controlγ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβpeptides without affecting otherγ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators ofγ-secretase activity have been discovered that spare theεcleavage of APP and other substrates while decreasing the production of Aβ42. Multiple chemical classes ofγ-secretase modulators have been identified which differ in the pattern of Aβpeptides produced. Ideally, modulators will allow theεcleavage of all substrates while shifting APP cleavage from Aβ42and other highly amyloidogenic Aβpeptides to shorter and less neurotoxic forms of the peptides without altering the total Aβpool. Here, we compare chemically distinct modulators for effects on APP processing andin vivoactivity.

scholarly journals Immunological Aspects and Anti-Amyloid Strategy for Alzheimer’s Dementia

2013 ◽  
Vol 64 (4) ◽  
pp. 603-608 ◽  
Author(s):  
Rajka M. Liščić
Keyword(s):  
The Elderly ◽  
Alzheimer’S Dementia ◽  
Paper Briefly ◽  
Complement Components ◽  
Synaptic Loss ◽  
Alzheimer's Dementia ◽  
Amyloid Deposits ◽  
Presymptomatic Stage ◽  
The Brain

Abstract Alzheimer’s dementia (AD) is the most common form of dementia among the elderly, accounting for at least two-thirds of all dementia cases. It represents a costly burden, since its global prevalence is estimated at 24 million cases. Amyloid beta or Aβ plaques and neurofibrillary tangles define AD pathologically but do not fully explain it, because dementia may also be caused by inflammation resulting in neuronal, axonal synaptic loss and dysfunction. An important component of AD pathophysiology are amyloid plaques surrounded by activated microglia, cytokines, and complement components, suggesting inflammation. In the diagnosis of AD, cerebrospinal fluid markers, especially in vivo amyloid measurements, contribute to an accurate assessment of AD pathology and differential diagnosis. Aβ levels are a very good marker for the presence of amyloid deposits in the brain, while total tau and phosphorylated tau are useful for the detection of neurodegeneration. The implementation of anti-amyloid therapy and other disease-modifying interventions may have immense clinical impact if initiated at an early or presymptomatic stage of AD, before significant brain damage occurs. This paper briefly reviews the abovementioned topics and provides recommendations for future studies.

scholarly journals Nutrient signaling pathways regulate amyloid clearance and synaptic loss in Alzheimer’s disease

2020 ◽  
Author(s):  
Mrityunjoy Mondal ◽  
Jitin Bali ◽  
Makis Tzioras ◽  
Rosa C. Paolicelli ◽  
Ali Jawaid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Pathological State ◽  
Amyloid Formation ◽  
Synaptic Loss ◽  
Synapse Loss ◽  
Human Neurons ◽  
Nutrient Signaling

SummaryExtra-cellular accumulation of Amyloid-β (Aβ) plaques is causatively associated with Alzheimer’s disease (AD). However, mechanisms that mediate the pre-pathological state of amyloid plaque formation remain elusive. Here, using paired RNAi and kinase inhibitor screens, we discovered that AKT-mediated insulin/nutrient signaling suppresses lysosomal clearance of Aβ and promotes amyloid formation. This mechanism is cell-autonomous and functions in multiple systems, including iPSC-derived human neurons and in vivo. Nutrient signaling regulates amyloid formation via distinct lysosomal functional mechanisms, while enhanced amino acid signaling promotes amyloid formation by transcriptionally suppressing lysosome biogenesis, and high intracellular cholesterol levels suppress lysosomal clearance of amyloid by increasing the number of non-functional lysosomes. The nutrient signaling pathway, present in both neurons and microglia, regulates lysosomal clearance of amyloid and microglia mediated synapse loss, both in vitro and in vivo. Clinically, older hyperlipidemic patients showed less synapse loss through microglia and performed better in cognitive tests. Thus, our results reveal a bi-partite cellular quality control system regulated by the insulinnutrient signaling that in neurons regulates Aβ peptide clearance and in microglia regulates synaptic loss, both processes causally associated with AD. Our results also caution against reducing amyloid through such processes as this might also result in synapse loss.

Abstract 582: A Novel Adipocytokine, Omentin, Prevents Monocrotaline-induced Pulmonary Arterial Hypertension In Rats

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
kyosuke kazama ◽  
Muneyoshi Okada ◽  
Hideyuki Yamawaki
Keyword(s):  
Inflammatory Responses ◽  
Ex Vivo ◽  
Negative Relationship ◽  
Weight Ratio ◽  
Vascular Wall ◽  
Structural Remodeling ◽  
Pulmonary Arterial ◽  
Hypertension Development

Background: Omentin is a novel adipocytokine mainly expressed in visceral rather than subcutaneous adipose tissue. Several epidemiological reports demonstrate the negative relationship between serum omentin level and occurrence of obesity, type 2 diabetes and hypertension. Increase of inflammatory responses, contractile reactivity and structural remodeling of vascular wall contributes to hypertension development. Our in vitro and ex vivo studies previously demonstrated that omentin prevented those hypertension-related pathological processes. In addition, our in vivo study demonstrated that intravenously injected omentin acutely inhibited agonists-induced increases of blood pressure in rats. However, the chronic effects of omentin on hypertension development are not determined. In the present study, we tested the hypothesis that chronic omentin treatment may prevent monocrotaline (MCT)-induced pulmonary arterial (PA) hypertension (PAH). Methods and Results: MCT-induced PAH was induced by a single intraperitoneal injection of MCT (60 mg/kg) to rats. Omentin (18 μg/kg/day) was intraperitoneally treated for 14 days. Chronic omentin inhibited MCT-induced increases in PA pressure (n=8-10, p<0.05). Omentin inhibited MCT-induced increases in right ventricular hypertrophy (n=6-8, p<0.01) as well as lung to body weight ratio (n=8, p<0.01). Histologically, omentin inhibited MCT-induced PA hyperplasia (n=8, p<0.01). Omentin prevented the impairment of both endothelium-dependent and-independent relaxations mediated by acetylcholine and sodium nitroprusside, respectively (n=7-13, p<0.01). Conclusion: We for the first time demonstrate that chronic omentin treatment inhibits MCT-induced PAH in rats via preventing endothelial dysfunction and/or vascular structural remodeling.

In Vitro and In Vivo Neuroprotective Effects of Etifoxine in β-Amyloidinduced Toxicity Models

2020 ◽  
Vol 19 (3) ◽  
pp. 227-240 ◽  
Author(s):  
Veronique Riban ◽  
Johann Meunier ◽  
Dorothee Buttigieg ◽  
Vanessa Villard ◽  
Marc Verleye
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Memory Test ◽  
Neuronal Cultures ◽  
Tau Hyperphosphorylation ◽  
Mice Model ◽  
Neuroprotective Effects ◽  
Synaptic Loss

Aim: The aim of this study is to examine the effect of etifoxine on β-amyloid-induced toxicity models. Background: Etifoxine is an anxiolytic compound with a dual mechanism of action; it is a positive allosteric modulator of GABAergic receptors as well as a ligand for the 18 kDa mitochondrial Translocator Protein (TSPO). TSPO has recently raised interest in Alzheimer’s Disease (AD), and experimental studies have shown that some TSPO ligands could induce neuroprotective effects in animal models. Objective: In this study, we examined the potential protective effect of etifoxine in an in vitro and an in vivo model of amyloid beta (Aβ)-induced toxicity in its oligomeric form, which is a crucial factor in AD pathologic mechanisms. Method: Neuronal cultures were intoxicated with Aβ1-42, and the effects of etifoxine on oxidative stress, Tau-hyperphosphorylation and synaptic loss were quantified. In a mice model, behavioral deficits induced by intracerebroventricular administration of Aβ25-35 were measured in a spatial memory test, the spontaneous alternation and in a contextual memory test, the passive avoidance test. Results: In neuronal cultures intoxicated with Aβ1-42, etifoxine dose-dependently decreased oxidative stress (methionine sulfoxide positive neurons), tau-hyperphosphorylation and synaptic loss (ratio PSD95/synaptophysin). In a mice model, memory impairments were fully alleviated by etifoxine administered at anxiolytic doses (12.5-50mg/kg). In addition, markers of oxidative stress and apoptosis were decreased in the hippocampus of these animals. Conclusion: Our results have shown that in these two models, etifoxine could fully prevent neurotoxicity and pathological changes induced by Aβ. These results confirm that TSPO ligands could offer an interesting therapeutic approach to Alzheimer’s disease.

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