Rosiglitazone Improves Spatial Memory and Decreases Insoluble Aβ1–42 in APP/PS1 Mice

How dependent is synaptic plasticity on microglial phenotype?

“…In contrast, albeit in a different model, APP/PS1 mice, microglial ablation appeared to have no effect on amyloidosis (Grathwohl et al, 2009). In the same model, we found that mRNA expression of IL-1, CD68 and CD11b, as well as the numbers of CD11b + CD80 + and CD11b + MHCII + cells, were increased in brain tissue from 7-9 month-old APP/PS1 mice, and that this was accompanied by evidence of A accumulation (Gallagher et al, 2013;O'Reilly and Lynch, 2012). In a separate study in 6 month-old APP/PS1 mice, we observed increases in concentrations of soluble and insoluble A 1-40 and A 1-42 but no increase in CD11b mRNA or in the number of CD11b + CD80 + or CD11b + CD86 + cells in the brain (McManus et al, 2014).…”

Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice

“…However, subsequent studies using PPAR agonists in several AD mouse models had variable success in observing changes in A␤ levels. Several studies using various treatment paradigms with PPAR␥ agonists observed decreases in soluble A␤ species (45,46), plaques (47,48) or both (27,36,49,50), and others reported decreased intracellular A␤ (51,52). However, there were also cases where PPAR␥ agonists exhibited no measurable effect on A␤ pathology (53)(54)(55).…”

“…LXR (9, 13, 18, 20 -24) and PPAR␥ (27,36,46,48,50,52,55,59,60) agonists have been reported to ameliorate memory deficits using a variety of tests in a range of mouse models. It should be noted, however, that Nicolakakis et al (53), Masciopinto et al (59), and Papadopoulos et al (54) reported no behavioral improvements after treating mice with pioglitazone.…”

Insulin resistance in Alzheimer's disease

“…For example, hippocampal insulin signaling, energy metabolism, and AMPK function, are similarly dysregulated in an APP/PS1 model (Pedros et al, 2014). Using PPARγ agonists, we and others have demonstrated that PPARγ agonism improves cognitive performance in these AD mouse models, predominantly in tasks that require intact hippocampal ERK signaling (Escribano et al, 2009; O'Reilly and Lynch, 2012; Pedersen et al, 2006; Rodriguez-Rivera et al, 2011). Cognitive enhancement has been shown to be accompanied by improved AD biomarker profiles: alleviation of amyloid and tau pathology (Escribano et al, 2010; Jiang et al, 2012; Kummer et al, 2014; Mandrekar-Colucci et al, 2012; O'Reilly and Lynch, 2012), reduced neuroinflammation (Escribano et al, 2010; Prakash and Kumar, 2014; Yin et al, 2013), increased antioxidant protection (Nicolakakis et al, 2008; Yin et al, 2013), amelioration of central insulin resistance (Masciopinto et al, 2012; Yin et al, 2013), and normalization of several transcripts and proteins related to ERK and insulin signaling in the hippocampus, including reversal of down-regulated PPARγ (Denner et al, 2012).…”