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  • However for a molecular target to be useful in AD

    2024-05-18

    However, for a molecular target to be useful in AD, it must rescue behavioral as well as biochemical insults. In humans, AD memory impairments typically declare themselves initially as disruption of episodic memory and consolidation of new memories, eventually progressing to global cognitive decline. Methods to assess analogous domains in rodent models are numerous, but to assess whether 5LO rescued the altered behavioral phenotype in AD mouse models, we selected the Y-maze exploratory behavior, and 24-h fear-conditioned memory recall. Aberration in Y-maze exploratory behavior represents impairment in short-term working memory while fear-conditioned memory impairment assesses hippocampal-dependent and hippocampal-independent memory building processes. In line with our data on synaptic integrity and LTP, 5LO inhibition and knockout restored learning and memory impairments in the transgenic mice as assessed by these paradigms to a level indistinguishable from their wild-type controls (Chu et al., 2012a, Chu et al., 2012b, Giannopoulos et al., 2014). Interestingly, a recent paper showed that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, the authors demonstrate that the effect is mediated through inhibition of the leukotriene receptor GPR17. This work illustrates that inhibition of 5LO pathway signaling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation opportunities of inhibitor of this pathway for the treatment of dementias (Marschallinger et al., 2015).
    5LO and GSAP The recent discovery of a γ-secretase activating protein (GSAP) which interacts with γ-secretase complex to facilitate Aβ formation without affecting Notch has established it as a new relevant target for a viable and safer in vivo anti-Aβ therapy (He et al., 2010, Deatherage et al., 2012). GSAP is increased in post-mortem nm to lb tissues of AD patients, and its pharmacological or genetic inhibition results in an amelioration of the AD-like amyloidotic phenotype in transgenic mouse models of the disease (Satoh et al., 2012, Chu et al., 2014a). The active form of GSAP is a 16kDa protein deriving from a C-terminal fragment of a larger precursor protein of 110kDa via a caspase-3 mediated cleavage (Chu et al., 2014b). Recent experimental evidence suggested for the first time that 5LO besides acting as a modulator of Aβ formation by regulating the transcription of the γ-secretase complex, it also behaves as an endogenous regulator of levels and availability of the GSAP 16kDa. In particular it was demonstrated that 5LO by activating caspase 3 regulates the proteolytic processing of precursor form of GSAP (110kDa) with the final formation of its active fragment (Fig. 3). These results were confirmed in vivo by using transgenic mouse models of AD in which 5LO level and activity were modulated genetically or pharmacologically (Chu et al., 2015).
    Implications of lipoxygenases as therapeutic targets for Alzheimer’s disease
    Acknowledgements The work from the author’s lab described in this article was supported in part by grants from the National Institute of Health, the Alzheimer’s Association and the Alzheimer’s Art Quilt Initiative.
    Introduction Sepsis is a major cause of death in intensive care units [1], [2], [3]. Although sepsis has been in the focus of research during the last decade, only little progress has been made towards its therapy [4]. The disease is characterized by an initial hyper-inflammatory phase, exemplified by an uncontrolled, excessive release of pro-inflammatory cytokines and mediators such as reactive oxygen species (ROS) or nitric oxide (NO) [5]. Moreover, the complement system and the coagulation cascade get activated [6]. Already starting during the hyper-inflammatory phase, anti-inflammatory principles increase and finally overwhelm pro-inflammatory responses thus, causing a hypo-inflammatory period [7]. Now, the immune response is significantly impaired by T cell depletion via apoptosis as well as macrophage desensitization [8], [9]. Interestingly, the removal of apoptotic cells by macrophages known as efferocytosis, causes a macrophage phenotype shift from classically activated (M1) to polarized macrophages (M2 MΦ) [10]. M2-type MΦ, also known as alternatively activated MΦ show an expression profile, which fosters wound healing and resolution of inflammation [11], [12]. As a consequence, their pathogen elimination capacity is low, which allows recurrence of the primary or the development of new opportunistic secondary infections in this phase of sepsis [13]. For this reason, therapy approaches shifting the macrophage phenotype from M2 to M1 in the hypo-inflammatory phase are important for a successful treatment regime. Along those lines, knowledge provoking the M1 to M2 phenotype shift may provide new concepts for an optimized therapy protocol.