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

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.

Reassessment of Pioglitazone for Alzheimer’s Disease

“…The PPARγ receptor is widely distributed the brain ( Braissant et al, 1996 ; Moreno et al, 2004 ; Gofflot et al, 2007 ; Sarruf et al, 2009 ; Morales-Garcia et al, 2011 ) and is crucial for learning ( He et al, 2009 ; Jahrling et al, 2014 ). Activation of the receptor enhances astrocyte/neuron metabolic coupling ( Dello Russo et al, 2003 ; Izawa et al, 2009 ; Cowley et al, 2012 ), promotes formation of dendritic spines ( Brodbeck et al, 2008 ), repairs synaptic failure ( Chen et al, 2015 ; Moosecker et al, 2019 ), corrects LTP impairment ( Cowley et al, 2012 ; Chen et al, 2015 ), and overcomes the pro-inflammatory, pro-oxidant milieu in the CNS that is central to the pathogenesis of AD. This topic has been reviewed previously ( Galimberti and Scarpini, 2017 ; Cai et al, 2018 ; Villapol, 2018 ; Khan et al, 2019 ).…”

“…Neurofibrillary tangles are correlated with neuronal dysfunction and brain atrophy more directly than are amyloid deposits ( Brion, 1998 ; Jack et al, 2018 ). Pioglitazone inhibited tau phosphorylation ( Cho et al, 2013 ; Hamano et al, 2016 ; Moosecker et al, 2019 ) and oligomerization ( Hamano et al, 2016 ) in cell-based tauopathy models, and in pre-clinical mouse models ( Escribano et al, 2010 ; Searcy et al, 2012 ). It also blocked misrouting of tau to dendritic spines in vitro ( Moosecker et al, 2019 ).…”

“…Pioglitazone inhibited tau phosphorylation ( Cho et al, 2013 ; Hamano et al, 2016 ; Moosecker et al, 2019 ) and oligomerization ( Hamano et al, 2016 ) in cell-based tauopathy models, and in pre-clinical mouse models ( Escribano et al, 2010 ; Searcy et al, 2012 ). It also blocked misrouting of tau to dendritic spines in vitro ( Moosecker et al, 2019 ). The PPARγ-specific antagonist GW9662 blocked these effects, confirming they were PPARγ receptor-dependent.…”

A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

“…NRMA-7 is the prodrug of dual PPAR/ agonist tesaglitazar, and PPAR agonists have been shown to protect dopaminergic neurons and reduce amyloid plaque burden. [21][22][23][24] However, tesaglitazar failed in clinical trials due to renal and cardiac safety issues, making tesaglitazar an ideal candidate for a drug that may benefit from this prodrug strategy. [25][26] Indeed, after seven days of dosing prodrug NRMA-7 was shown to significantly upregulate the PPAR target gene Pgc1- (PPAR gamma coactivator 1 alpha) in the brain, while having no effect on expression of Fasn (fatty acid synthase) in the kidney (Figure 6C+D).…”

Amyloid precursor protein, an androgen‐regulated gene, is targeted by RNA‐binding protein PSF/SFPQ in neuronal cells

“…In the present study, we explored the regulatory mechanisms of APP expression associated with AR and PSF using SH-SY5Y cells derived from the human neurons (Butler, Leigh, & Gallo, 2001;Matsumoto et al, 2006), which express endogenous AR and exhibit androgendependent cell growth (Sun et al, 2017). Moreover, as in previous reports (Ke et al, 2012;Liang et al, 2019;Moosecker et al, 2019), the expression and function of several key factors such as APP and Tau proteins have been analyzed in SH-SY5Y cells. Therefore, this cell line is suitable for investigating molecular mechanisms associated with neurodegenerative diseases such as Alzheimer's disease.…”