scholarly journals Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice

2015 ◽  
Vol 290 (35) ◽  
pp. 21591-21602 ◽  
Author(s):  
Rebecca Skerrett ◽  
Mateus P. Pellegrino ◽  
Brad T. Casali ◽  
Laura Taraboanta ◽  
Gary E. Landreth
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Liver X Receptor ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity

2019 ◽  
Vol 13 ◽  
Author(s):  
Susanne Moosecker ◽  
Patrícia Gomes ◽  
Chrysoula Dioli ◽  
Shuang Yu ◽  
Ioannis Sotiropoulos ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Neuronal Cultures ◽  
Peroxisome Proliferator ◽  
Synaptic Loss ◽  
Peroxisome Proliferator Activated Receptor ◽  
Primary Mouse ◽  
Synaptic Pathology ◽  
Pparγ Agonists

Type 2 diabetes increases the risk for dementia, including Alzheimer’s disease (AD). Pioglitazone (Pio), a pharmacological agonist of the peroxisome proliferator-activated receptor γ (PPARγ), improves insulin sensitivity and has been suggested to have potential in the management of AD symptoms, albeit through mostly unknown mechanisms. We here investigated the potential of Pio to counter synaptic malfunction and loss, a characteristic of AD pathology and its accompanying cognitive deficits. Results from experiments on primary mouse neuronal cultures and a human neural cell line (SH-SY5Y) show that Pio treatment attenuates amyloid β (Aβ)-triggered the pathological (mis-) processing of amyloid precursor protein (APP) and inhibits Aβ-induced accumulation and hyperphosphorylation of Tau. These events are accompanied by increased glutamatergic receptor 2B subunit (GluN2B) levels that are causally linked with neuronal death. Further, Pio treatment blocks Aβ-triggered missorting of hyperphosphorylated Tau to synapses and the subsequent loss of PSD95-positive synapses. These latter effects of Pio are PPARγ-mediated since they are blocked in the presence of GW9662, a selective PPARγ inhibitor. Collectively, these data show that activated PPARγ buffer neurons against APP misprocessing, Tau hyperphosphorylation and its missorting to synapses and subsequently, synaptic loss. These first insights into the mechanisms through which PPARγ influences synaptic loss make a case for further exploration of the potential usefulness of PPARγ agonists in the prevention and treatment of synaptic pathology in AD.

Presenilin 1 Regulates the Processing of β-Amyloid Precursor Protein C-Terminal Fragments and the Generation of Amyloid β-Protein in Endoplasmic Reticulum and Golgi†

Biochemistry ◽  
1998 ◽  
Vol 37 (47) ◽  
pp. 16465-16471 ◽  
Author(s):  
Weiming Xia ◽  
Jimin Zhang ◽  
Beth L. Ostaszewski ◽  
William Taylor Kimberly ◽  
Peter Seubert ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Amyloid Precursor Protein ◽  
Protein C ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Β Amyloid

scholarly journals Oral Treponema denticola infection induces Aβ1-40 and Aβ1-42 accumulation in the hippocampus of C57BL/6 mice

2021 ◽  
Author(s):  
Xinyi Su ◽  
Zhiqun Tang ◽  
Yuqiu Liu ◽  
Wanzhi He ◽  
Jiapei Jiang ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Porphyromonas Gingivalis ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Central Component ◽  
Treponema Denticola ◽  
Periodontal Pathogens ◽  
The Brain

Abstract Accumulation of amyloid-β (Aβ) in the brain is a central component of pathology in Alzheimer’s disease. A growing number of evidences demonstrate close associations between periodontal pathogens including Porphyromonas gingivalis (P. gingivalis) and Treponema denticola (T. denticola) and AD. However, the effect and mechanisms of T. denticola on accumulation of Aβ remain to be unclear. In this study, we demonstrated that T. denticola was able to enter brain and act directly on nerve cells resulting in intra and extracellular Aβ1−40 and Aβ1−42 accumulation in the hippocampus of C57BL/6 mice by selectively activating both β-secretase and γ-secretase. Furthermore, both KMI1303, an inhibitor of β- secretase, as well as DAPT, an inhibitor of γ- secretase were found to be able to inhibit the effect of T. denticola on Aβ accumulation in N2a neuronal cells. Overall, it is concluded that T. denticola increases the expression of Aβ1−42 and Aβ1−40 by its regulation on beta-site amyloid precursor protein cleaving enzyme-1 and Presenilin 1.

scholarly journals Role of peroxisome proliferator-activated receptor γ in amyloid precursor protein processing and amyloid β-mediated cell death

2005 ◽  
Vol 391 (3) ◽  
pp. 693-698 ◽  
Author(s):  
Cristina d'Abramo ◽  
Sara Massone ◽  
Jean-Marc Zingg ◽  
Antonio Pizzuti ◽  
Philippe Marambaud ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aβ Amyloid ◽  
Pparγ Agonists ◽  
Amyloid Cascade

Recent data indicate that PPARγ (peroxisome proliferator-activated receptor γ) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease. In the present study we show that PPARγ overexpression in cultured cells dramatically reduced Aβ (amyloid-β) secretion, affecting the expression of the APP (Aβ precursor protein) at a post-transcriptional level. APP down-regulation did not involve the pathway of the secretases and correlated with a significant induction of APP ubiquitination. Additionally, we demonstrate that PPARγ was able to protect the cells from H2O2-induced necrosis by decreasing Aβ secretion. Taken together, our results indicate a novel mechanism at the basis of the neuroprotection shown by PPARγ agonists and an additional pathogenic role for Aβ accumulation.

TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β42 Lowering by GSM-10h

2011 ◽  
Vol 8 (1-2) ◽  
pp. 15-24 ◽  
Author(s):  
Ishrut Hussain ◽  
David C. Harrison ◽  
Julie Hawkins ◽  
Trevor Chapman ◽  
Ian Marshall ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Presenilin 1

scholarly journals The Role of Presenilin-1 in the γ-Secretase Cleavage of the Amyloid Precursor Protein of Alzheimer's Disease

2000 ◽  
Vol 275 (3) ◽  
pp. 1525-1528 ◽  
Author(s):  
Jean-Noël Octave ◽  
Rachid Essalmani ◽  
Bernadette Tasiaux ◽  
Jean Menager ◽  
Christian Czech ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Presenilin 1
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