Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity
Year: 2019
Type: article
Abstract: 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.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,950
Awards: G1167214205, G1516346500, G1578237752, G1763632427, G2260414028, G2440504136, G274581676, the role of exosoes in stress driveu tampathology - Exosome dynamics in stress-driven brain pathology: a novel link between Alzheimer´s disease and depression, G3326568298, G3786582701, G3840324753, G4425158674, New avenues for the development of personalized medical interventions for neurological, oncologic and surgical disorders – “PersonalizedNOS”, Switchbox: Maintaining health in old age through homeostasis, G5224927334, Projecto Estratégico - LA 26 - 2013-2014, G5454278309, UID/Multi/50026 .: ICVS/3B?s - Laboratório Associado, Instituto de Ciências da Vida e da Saúde / Grupo de Investigação em Biomateriais, Bio, G7584003722, G7965899483, G8757879299, G8868700560
OpenAlex ID: W2949635040