scholarly journals A new blood‐based biomarker of Aβ clearance: The monocyte Aβ mid‐domain assay

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Erik Christensen ◽  
Marianne Wettergreen ◽  
Silje Bøen Torsetnes ◽  
Berglind Gisladottir ◽  
Tormod Fladby
Keyword(s):  
Aβ Clearance

scholarly journals Successful electroconvulsive therapy for depression in a man with cerebral amyloid angiopathy

2021 ◽  
Vol 14 (2) ◽  
pp. e238922
Author(s):  
Geert Schurgers ◽  
Baer M G Arts ◽  
Alida A Postma ◽  
Anna de Kort
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Electroconvulsive Therapy ◽  
Severe Depression ◽  
Amyloid Angiopathy ◽  
Amyloid Beta Protein ◽  
Cerebral Blood Vessels ◽  
Safety Measures ◽  
Aβ Clearance ◽  
Cerebral Amyloid ◽  
The Impact

Cerebral amyloid angiopathy (CAA) is a condition characterised by accumulation of amyloid beta protein (Aβ) in the wall of cerebral blood vessels which increases the risk of intracranial haemorrhage and contributes to cognitive impairment. We describe the case of a man around the age of 70 with ‘probable’ CAA according to the modified Boston criteria and severe depression whose depression was treated successfully with electroconvulsive therapy (ECT). To the best of our knowledge, there are no earlier published reports of ECT in a patient with CAA. We briefly discuss possible safety measures for these patients, the impact of ECT on cognition in CAA and a possible influence of ECT on Aβ clearance.

scholarly journals Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Nicola Davis ◽  
Bibiana C. Mota ◽  
Larissa Stead ◽  
Emily O. C. Palmer ◽  
Laura Lombardero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Culture Media ◽  
Ex Vivo ◽  
Wild Type ◽  
Insulin Degrading Enzyme ◽  
Ex Vivo Model ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Clearance ◽  
5Xfad Mice

Abstract Background Astrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear. Methods To explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h. Results Treatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L-AAA treatment in all groups analyzed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control. Conclusions Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.

scholarly journals Synthesis and Biological Evaluation of Hydroxylated Monocarbonyl Curcumin Derivatives as Potential Inducers of Neprilysin Activity

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 955
Author(s):  
Dimitris Matiadis ◽  
See-Ting Ng ◽  
Eric H.-L. Chen ◽  
Georgia Nigianni ◽  
Veroniki P. Vidali ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Therapeutic Strategy ◽  
Specific Inhibitor ◽  
Biological Evaluation ◽  
Lead Compound ◽  
Cleavage Activity ◽  
Curcumin Derivatives ◽  
Aβ Clearance ◽  
Activity Enhancement ◽  
Synthesis And Biological Evaluation

Background: Alzheimer’s disease (AD) involves impairment of Aβ clearance. Neprilysin (NEP) is the most efficient Aβ peptidase. Enhancement of the activity or expression of NEP may provide a prominent therapeutic strategy against AD. Aims: Ten hydroxylated monocarbonyl curcumin derivatives were designed, synthesized and evaluated for their NEP upregulating potential using sensitive fluorescence-based Aβ digestion and inhibition assays. Results: Compound 4 was the most active one, resulting in a 50% increase in Aβ cleavage activity. Cyclohexanone-bearing derivatives exhibited higher activity enhancement compared to their acetone counterparts. Inhibition experiments with the NEP-specific inhibitor thiorphan resulted in dramatic cleavage reduction. Conclusion: The increased Aβ cleavage activity and the ease of synthesis of 4 renders it an extremely attractive lead compound.

scholarly journals Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

2021 ◽  
Vol 13 ◽  
Author(s):  
Dongmei Wu ◽  
Yang Hu ◽  
Min Song ◽  
Gongbo Li
Keyword(s):  
Amyloid Beta ◽  
Critical Role ◽  
Liver X Receptor ◽  
Dynamics Simulation ◽  
Atp Binding ◽  
Atp Binding Cassette Transporter ◽  
Liver X Receptor Α ◽  
Aβ Clearance ◽  
Atp Binding Cassette

Abnormal amyloid beta (Aβ) clearance is a distinctive pathological mechanism for Alzheimer’s disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aβ clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aβ clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aβ clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aβ to evaluate Aβ consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aβ clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aβ clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.

IL-18 induced IL-23/IL-17 expression impairs Aβ clearance in cultured THP-1 and BV2 cells

Cytokine ◽  
2019 ◽  
Vol 119 ◽  
pp. 113-118 ◽  
Author(s):  
Jin-Mei Chen ◽  
Qing-Wei Li ◽  
Guo-Xin Jiang ◽  
Jian-Sheng Liu ◽  
Qi Cheng
Keyword(s):  
Bv2 Cells ◽  
Aβ Clearance

scholarly journals The amyloid-β degradation intermediate Aβ34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer’s disease

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Tunahan Kirabali ◽  
Serena Rigotti ◽  
Alessandro Siccoli ◽  
Filip Liebsch ◽  
Adeola Shobo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Brain Capillaries ◽  
Post Mortem Brain ◽  
Brain Pericytes ◽  
Aβ Clearance ◽  
Disease Stages

AbstractAn impairment of amyloid β-peptide (Aβ) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer’s disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of Aβ40 and Aβ42 results in the formation of a common Aβ34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of Aβ34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of Aβ34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, Aβ34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated Aβ34 immunoreactivity was largely lost. Aβ34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with Aβ40, but not with Aβ42 levels. Moreover, a significantly decreased Aβ34/Aβ40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of Aβ40 to Aβ34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of Aβ34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of Aβ34 levels upon treatment with recombinant Aβ40 peptides while Aβ34 production was impaired when Aβ40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that Aβ34 is generated by a novel BACE1-mediated Aβ clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.

scholarly journals Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis

2018 ◽  
Vol 15 (7) ◽  
pp. 637-642 ◽  
Author(s):  
M.A. Pappolla ◽  
E. Matsubara ◽  
R. Vidal ◽  
J. Pacheco-Quinto ◽  
B. Poeggeler ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lymph Nodes ◽  
Transgenic Mouse ◽  
Lymphatic System ◽  
Transgenic Mouse Model ◽  
Axillary Lymph ◽  
Prior Report ◽  
Aβ Aggregation ◽  
Aβ Clearance ◽  
The Brain

Background: It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone. Objective: To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular “waste” products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes. Methods: For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the Aβ precursor protein (APP) in the brain. We examined levels of Aβ in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. Aβ levels were also measured in the brain and in multiple tissues. Results: Clearance of Aβ peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric Aβ40 and an increasing trend in Aβ42 in cervical and axillary lymph nodes of treated mice. 2- Statistically significant decreases in oligomeric Aβ40 and a decreasing trend Aβ42 in the brain. Conclusion: The data expands on our prior report that the lymphatic system participates in Aβ clearance from the brain. We propose that abnormalities in Aβ clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i.e., indole- 3-propionic acid) are known to inhibit Aβ aggregation although they do not reverse aggregated Aβ or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.

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