Alzheimer’s disease (AD) is a neurodegenerative disorder associated with accumulation of the β-amyloid peptide (Aβ). Aβ has been shown to impair hippocampal long-term potentiation (LTP) in vivo and in vitro (Freir et al. 2003; Costello & Herron, 2003). LTP is an activity-dependent increase in synaptic efficacy, widely accepted as a cellular model of memory. Peroxisome proliferator activated receptors (PPARs) are a class of nuclear receptor transcription factors, regulated by mitogen activated protein kinases (MAPKs). PPARλ expression is elevated in AD (Kitamura et al. 1999), and PPAR agonists have been shown to prevent Aβ-stimulated activation of microglia and production of proinflammatory cytokines (Combs et al. 2000). We have identified a role for MAPKs in the depressant effects of Aβ on LTP in vitro (Costello & Herron, 2003). Here we investigate the effects of PPARλ agonists on synaptic transmission and on the Aβ[1-40]-mediated impairment of LTP.
Experiments were performed on hippocampal slices (350 µm) from humanely killed male Wistar rats (50-100g). The Schaffer collateral-commissural pathway was stimulated at 0.033 Hz and field excitatory postsynaptic potentials (EPSPs) were recorded in area CA1. LTP was induced by applying high frequency stimuli (HFS; 10 trains of 10 pulses at 200 Hz, repeated 3 times at 20 s intervals). Control LTP was recorded 1 h post-HFS (167 ± 4 %, %EPSP slope ± S.E.M., n = 8).
Aβ[1-40] (200 nM) significantly reduced LTP (137 ± 6%, n = 5, P < 0.001 repeated measures ANOVA), when applied 1 h pre-HFS. The PPARλ agonist troglitazone (20 µM) significantly enhanced LTP (174 ± 10 %, n = 5, P < 0.05), when applied 30 min prior to HFS. Ciglitazone (20 µM) however did not affect LTP significantly (161 ± 9 %, n = 4), but enhanced baseline transmission (108 ± 4 %, n = 4, P < 0.05) 30 min following application. The endogenous PPARλ agonist, 15-deoxy-Δ12,14PGJ2 (5 µM), reduced LTP significantly (143 ± 2 %, n = 5, P < 0.001), but also increased baseline transmission (109 ± 3 %, n = 5, P < 0.05) when present for 30 min. When slices were perfused with each agonist for 30 min and Aβ[1-40] for a further 60 min, the depression in LTP was significantly attenuated when compared with Aβ[1-40] alone (troglitazone+Aβ: 163 ± 5 %, n = 5, P < 0.005; ciglitazone+Aβ: 152 ± 9 %, n = 5, P < 0.0001; PGJ2 +Aβ: 164 ± 9 %, n = 4, P < 0.05), measured 1 h post-HFS. However, in the presence of ciglitazone and Aβ[1-40], LTP did not differ significantly compared with control values or Aβ[1-40] alone (152 ± 9%, n = 5). This suggests that enhancing PPARλ activity may reduce the impairment of LTP mediated by Aβ[1-40]. We also suggest involvement of PPARλ agonist in the regulation of synaptic transmission and LTP in the CA1.
This work was supported by HRB Ireland and Enterprise Ireland