br LO and the secretase complex Supporting this concept duri

5LO and the γ-secretase complex Supporting this concept, during a recent trial testing the γ-secretase inhibitor semagacestat (LY 450139), AD patients actually experienced a functional decline compared to patients who took a placebo in addition to several other significant adverse effects (Doody et al., 2013). Thus, development of compounds able to selectively inhibit Aβ production without affecting the cleavage of other substrates is the most desirable approach for AD therapy to minimize the toxic effects. Therefore, to see if Notch was also affected in our system, we assayed whether its signaling pathway was altered in both our cellular and animal models. To our surprise, we found that 5LO-dependent modulation of γ-secretase is completely independent of Notch processing. While at the present time it is not known why a reduction in steady-state levels of γ-secretase induced by knockout or inhibition of 5LO reduces amyloid levels without altering Notch, our findings are in line with the novel concept of “modulatory action” of 5LO towards this secretase. Thus, recently a new class of drug has emerged as modulators and not direct inhibitors of the γ-secretase which would reduce Aβ formation without interfering with the processing of other biologically important substrates such as Notch (Wolfe, 2008). We speculate that 5LO activation may somehow alter membrane dynamics allowing greater access to APP than Notch processing, although this area 5LO neurobiology biology remains completely unexplored.
5-lipoxygenase modulation of the AD-like phenotype:
Neuroinflammation Altered inflammatory reactions are strongly associated with AD pathology and cognitive dysfunction. The dysregulation of inflammatory cytokines as well as immune Bleomycin A5 hydrochloride (i.e., microglia and astrocytes) activation in AD brains has been well-documented (Morales et al., 2013, Jo et al., 2014, Wright et al., 2013). Disruption of the 5LO pathway, either genetically or pharmacologically, reduces not only microglia, but also astrocytosis in the brains of AD transgenic mice (Lai et al., 2014, Chu et al., 2012a, Giannopoulos et al., 2014), which associated with a reduction in pro-inflammatory cytokine levels. An argument can be made that reduction in Aβ and tau pathology caused by 5LO inhibition independently predisposes AD transgenic animals to have reduced neuroinflammation at baseline. While this may be true to some extent, chronic lipopolysaccharide administration in AD animals lacking 5LO increases tau phosphorylation despite the fact that no γ-secretase elevation was observed, Aβ was reduced, microgliosis and astrocytosis, or brain levels of inflammatory cytokines were reduced to baseline (Joshi et al., 2014). These data suggest that the contribution of 5LO to the neuroinflammation does not depend exclusively on Aβ or tau.
5LO and AD synaptic function and memory impairment Data from transgenic mouse models of the disease as well as brains of AD patients have strongly suggested that the Aβ and tau neuropathologies compromise synaptic function, with such impairment occurring well before symptoms of the disease manifest (Giannopoulos and Praticò, 2015). This dysfunction is characterized by alteration in markers of presynaptic integrity, such as synaptophysin, as well as markers of post-synaptic integrity, such as post-synaptic density protein 95 (PSD-95), eventually leading to impairments in long-term potentiation (LTP), which is considered a marker of synaptic function. Presumably, if 5LO modulates Aβ and tau pathology, it would also alter synaptic integrity and LTP in AD animals. To see if this was the case, we continued our investigation of 5LO in the same AD animal models, focusing on these important aspects of the neurobiology of AD. First, we observed that overexpression of 5LO resulted in reduced synaptophysin and PSD-95, while inhibition and knockout of 5LO increased levels of these proteins in the brains of Tg2576 as well as 3xTg mice. To investigate whether this had functional relevance, we utilized an electrophysiological approach to see whether 5LO affected hippocampal LTP. While we confirmed previous reports showing that 3xTg animals have significant impairment in LTP when compared to wild-type control mice, next we showed that genetic absence of 5LO or its pharmacological blockade was both able to rescue this dysfunction, restoring LTP to the same levels of the wild-type mice (Chu et al., 2012a, Chu et al., 2012b, Giannopoulos et al., 2014).