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

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.SwitchBox Project, funded by the European Union (FP7-Health, Contract 259772) to OA, and by grants from the Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013), the European Regional Development Fund COMPETE (FCOMP-01-0124- FEDER-037298), Project NORTE-01-0145-FEDER-000013 (Portugal 2020 Partnership Agreement, European Regional Development Fund), FEDER funds from Competitiveness Factors Operational Programme (COMPETE), and grants from the Portuguese Foundation for Science and Technology (FCT) to IS (POCI-01-0145-FEDER-007038) and to PG (PD/BD/135271/2017). The funding agencies played no role in the design, execution or interpretation of the findings reported herein. SM was partly supported by a pre-doctoral fellowship from the Max Planck Society and received a Short-Term Scientific Mission bursary from COST Action MouseAge (BM1402