Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/62362

TitleActivated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity
Author(s)Moosecker, Susanne
Gomes, Patrícia
Dioli, Chrysoula
Yu, Shuang
Sotiropoulos, I.
Almeida, Osborne F. X.
KeywordsAlzheimer’s disease
Amyloid beta
Pioglitazone
PPARγ
Neurons
Synaptic degradation
Tau missorting
PPAR gamma
Issue date2019
PublisherFrontiers Media
JournalFrontiers in Cellular Neuroscience
CitationMoosecker, S., Gomes, P. A., Dioli, C., Yu, S., Sotiropoulos, I., & Almeida, O. F. (2019). Activated PPARγ abrogates misprocessing of amyloid precursor protein, Tau missorting and synaptotoxicity. Frontiers in Cellular Neuroscience, 13, 239.
Abstract(s)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.
TypeArticle
URIhttp://hdl.handle.net/1822/62362
DOI10.3389/fncel.2019.00239
ISSN1662-5102
e-ISSN1662-5102
Publisher versionhttps://www.frontiersin.org/articles/10.3389/fncel.2019.00239/full
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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