Cognitive Enhancing Treatment with a PPARγ Agonist Normalizes Dentate Granule Cell Presynaptic Function in Tg2576 APP Mice

Abstract

Hippocampal network hyperexcitability is considered an early indicator of Alzheimer's disease (AD) memory impairment. Some AD mouse models exhibit similar network phenotypes. In this study we focused on dentate gyrus (DG) granule cell spontaneous and evoked properties in 9-month-old Tg2576 mice that model AD amyloidosis and cognitive deficits. Using whole-cell patch-clamp recordings, we found that Tg2576 DG granule cells exhibited spontaneous EPSCs that were higher in frequency but not amplitude compared with wild-type mice, suggesting hyperactivity of DG granule cells via a presynaptic mechanism. Further support of a presynaptic mechanism was revealed by increased I-O relationships and probability of release in Tg2576 DG granule cells.Since we and others have shown that activation of the peroxisome proliferator-activated receptor gamma (PPAR␥) axis improves hippocampal cognition in mouse models for AD as well as benefitting memory performance in some humans with early AD, we investigated how PPAR␥ agonism affected synaptic activity in Tg2576 DG. We found that PPAR␥ agonism normalized the I-O relationship of evoked EPSCs, frequency of spontaneous EPSCs, and probability of release that, in turn, correlated with selective expression of DG proteins essential for presynaptic SNARE function that are altered in patients with AD. These findings provide evidence that DG principal cells may contribute to early AD hippocampal network hyperexcitability via a presynaptic mechanism, and that hippocampal cognitive enhancement via PPAR␥ activation occurs through regulation of presynaptic vesicular proteins critical for proper glutamatergic neurotransmitter release, synaptic transmission, and short-term plasticity.

Dihydromyricetin ameliorates the oxidative stress response induced by methylglyoxal via the AMPK/GLUT4 signaling pathway in PC12 cells

“…MG accumulates under conditions of hyperglycemia, impaired glucose metabolism or oxidative stress (Nenov et al, 2014). In this study, we demonstrated that DMY protected PC12 cells from MGinduced oxidative and glucose metabolic disorders.…”

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

“…Previously we showed that RSG diet ameliorates aberrant synaptic transmission and neuronal excitability in Tg2576 DG granule cells (Nenov et al, 2014, 2015). Treatment with RSG significantly restores repetitive firing in two types (type 1 and type 2) of electrophysiologically characterized DG granule cells via bi-directional modulation of spike after-depolarization (Nenov et al, 2014, 2015).…”

“…Treatment with RSG significantly restores repetitive firing in two types (type 1 and type 2) of electrophysiologically characterized DG granule cells via bi-directional modulation of spike after-depolarization (Nenov et al, 2014, 2015). Here, in order to characterize functional outcomes associated with changes in Tg2576 AIS expression profiles for PanNav channels, FGF14 and another AIS marker, Ankyrin-G, we assessed time to rise and time to decay half-amplitude of action potentials in two previously identified types of DG granule cells (Nenov et al, 2015; Tempia et al, 2015).…”

“…Stable isotope labeling was used to quantify differential phosphorylation between Tg2576 and Tg2576 on an RSG diet as previously described (Nenov et al, 2014; Sadygov et al, 2010; Wu et al, 2013). Briefly, the DG region of the hippocampus was dissected under magnification with a dissecting microscope, homogenized in TRIzol (Life Technologies), and resuspended in guanidine.…”

“…Likewise, RSG treatment rescues hippocampus-dependent cognitive function in the Tg2576 AD mouse model (Rodriguez-Rivera et al, 2011; Denner et al, 2012) by a mechanism that involves normalized intrinsic excitability and synaptic function of granule neurons in the dentate gyrus (DG), a critical location for new memory formation (Nenov et al, 2015). Dysregulation of the ERK-MAPK signaling pathway that subserves hippocampus-dependent cognition (Denner et al, 2012; Ahi et al, 2004; Atkins et al, 1998; Sweatt, 2004; McGaugh, 2000; Jahrling et al, 2014), the presynaptic VAMP-2 glutamate release machinery (Nenov et al, 2014), and voltage-gated ion channels (Nenov et al, 2015) may mediate the effect of RSG treatment on granule neuron function, but details of how PPARγ–agonism affects excitability in ion channel complexes are lacking. Because voltage-gated ion channels are the fundamental unit of excitability in the neuron, investigating how RSG treatment affects ion channel proteins may identify critical nodes in downstream pathways of Aβ pathology and provide useful information for therapeutic strategies (Rusinova et al, 2011; Imbrici et al, 2016; Catterall, 2012).…”