Overexpression of ABCA1 reduces the deposition of A in the PDAPP mouse model of AD [25]. we further found that short-term administration of PGA1 decreased the levels of the monomeric and oligomeric -amyloid protein (oA) in a cholesterol-dependent manner. In detail, PGA1 activated the peroxisome proliferator-activated receptor-gamma (PPAR) and ATP-binding cassette subfamily A member 1 (ABCA1) signalling pathways, promoting the efflux of cholesterol and decreasing the intracellular cholesterol levels. Through PPAR/ABCA1/cholesterol-dependent pathway, PGA1 decreased the expression of presenilin enhancer protein 2 (PEN-2), which is responsible for the production of A. More importantly, long-term administration of PGA1 remarkably decreased the formation of A monomers, oligomers, and fibrils. The actions of PGA1 on the production and deposition of A ultimately improved the cognitive decline of the amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice. Electronic supplementary material The online version of this article (10.1007/s13311-018-00704-1) contains supplementary material, which is available to authorized users. [14]. Because these effects are potentially neuroprotective, the therapeutic potential of PGA1 in neurodegenerative disorders, in which excitotoxicity may TDP1 Inhibitor-1 contribute to pathogenesis, has been evaluated using many models. However, further detailed studies have not yet been performed. AD is an age-related disorder characterized by the deposition of -amyloid protein (A), the presence of neurofibrillary tangles (NFTs), and degeneration of neurons in different brain regions, resulting in progressive cognitive dysfunction [15]. Various factors may be involved in the etiology, pathogenesis, and progression of AD [16]. Because this increasingly detailed understanding of AD pathogenesis has yet to lead to the development of an effective therapeutic intervention, novel approaches warrant urgent development and rigorous evaluation [17]. Refolo et al. revealed Rgs4 a correlation between hypercholesterolemia, an early risk factor for AD, with aberrant activation of -amyloid precursor protein (APP) processing pathways and increased A production [18]. Based on accumulating evidence, elevated cholesterol levels stimulated the activities of – and -secretases, and a low cholesterol environment inhibits the production of A [19]. In addition, a decreased incidence of AD is associated with the use of the cholesterol-lowering drugs, such as simvastatin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) [20]. Likewise, methyl–cyclodextrin, the cholesterol-extracting reagent strongly reduces intracellular and extracellular levels of A1-40 and A1-42 peptides in primary cultures of hippocampal neurons and mixed cortical neurons [21]. Interestingly, high cholesterol diets have the ability to accelerate the deposition of A even though cholesterol could not cross into the brain from the bloodstream in the brain of rabbits, guinea pigs, and rats [18]. To the reason, the effect of cholesterol on AD is recently found to be largely dependent on carriers and storage, such as apolipoprotein E (apoE), acyl-coenzyme A:cholesterol acyltransferase (ACAT), and ATP-binding cassette subfamily A member 1 (ABCA1) [22, 23]. In detail, ACAT has been regarded as a drug target of AD [24]. Overexpression of ABCA1 reduces the deposition of A in the PDAPP mouse model of AD [25]. Deletion of ABCA1 increases the deposition of A in the PDAPP mouse model of AD [26]. More directly, cholesterol is concentrated in the core of dendritic amyloid plaques (APs) [27]. All in all, cholesterol appears to TDP1 Inhibitor-1 play a key role in A aggregation via its transport. As the potential roles of cholesterol TDP1 Inhibitor-1 in the deposition of A, the molecules involved in regulating the metabolism of cholesterol should be further identified. To this end, a few studies have revealed a connection between PGs and cholesterol [28]. For example, 15d-PGJ2/PPAR/CD36 pathways participate in regulating the metabolism of cholesterol [29]. In addition, increased synthesis of PGs may also be involved in the niacin-induced activation of the PPAR/liver X receptor alpha (LXR)/ABCA1 pathway in adipocytes [30]. For ABCA1, it has the ability to modulate the cholesterol levels of cerebrospinal fluid (CSF) and influences the age at onset of AD [31]. Along these lines, the identification of a novel pathway that regulates ABCA1 expression may represent a new strategy for regulating A levels. PGA1 acts as a potent and specific ligand/activator of PPAR, and this pathway regulates lipid and lipoprotein metabolism. Therefore, does cholesterol mediate the neuroprotective effect of PGA1? Materials and Methods Reagents GW9662, a PPAR antagonist, was obtained from Sigma-Aldrich (St. Louis, MO). DIDS, an ABCA1 inhibitor, was purchased from Santa Cruz Biotechnology (Dallas, TX). PGA1.