In a study by the Landreth group the administration of
In a study by the Landreth group , the administration of bexarotene, a retinoid X receptor (RXR) agonist used as a treatment for cutaneous T cell lymphoma, reduced Aβ levels in the Acarbose and restored cognitive function in AD mouse models within only 7 days of treatment. Thus, bexarotene may be a promising treatment for AD. However, other studies [, , , ] have failed to fully replicate the results reported by the Landreth group. Furthermore, bexarotene displays a large number of serious side effects, such as hepatomegaly, hypertriglyceridemia, weight loss, and central hypothyroidism, which likely result from hepatic failure. Our group designed and synthesized a series of compounds using bexarotene as the lead compound, and screened out the novel small molecule OAB-14. We examined the effects of acute and chronic OAB-14 treatments on cognitive functions and Aβ levels in brain tissues from 8-month-old amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice. Although its negative effects have been reported, bexarotene is currently the only drug that rapidly increases Aβ clearance. Therefore, we chose it as a positive control drug in our experiments. Since Aβ accumulation in the brains of patients with AD induces other pathological changes, such as tau hyperphosphorylation, neuronal loss, neuroinflammation and synaptic degeneration [15,16], we also investigated the effects of OAB-14 on these pathological events in AD and addressed its safety concerns.
Materials and methods
Discussion Currently, the most accepted hypothesis regarding the aetiology of AD is the Aβ cascade hypothesis proposed by Hardy . According to this hypothesis, large amounts of Aβ deposits appear in the brains of patients with AD as the disease progresses and are related to the memory disorders observed in patients with AD. APP/PS1 double transgenic mice, which mimic the pathological hallmarks of AD in terms of Aβ deposition, have been widely used as an animal model of AD. In this study, we investigated the therapeutic effects of OAB-14 on Aβ-related pathology in 8-month-old APP/PS1 mice. In the present study, we evaluated image discrimination memory using the NOR test and spatial learning and memory using the MWM test. Acute and chronic OAB-14 treatments exerted remarkable effects on cognitive impairments in APP/PS1 mice. Using Aβ antibody staining and thioflavin S staining, we observed that OAB-14 treatments significantly decreased Aβ deposits in the hippocampus and cortex; ELISA also revealed that OAB-14 treatments reduced the levels of soluble and insoluble Aβ in the cortex of APP/PS1 mice. The following three main mechanisms of Aβ clearance have been reported: enzyme-mediated Aβ degradation, including NEP, IDE, ECE, etc.; receptor-mediated Aβ transport; and microglia-dependent phagocytosis. Based on accumulating evidence, microglia internalize soluble and fibrillar Aβ in vivo and in vitro by phagocytosis . Bexarotene increases the removal of soluble Aβ by microglia in an ApoE-dependent manner . As the primary lipid transporter in the brain, ApoE possess three allelic isoforms, including ApoE2, ApoE3 and ApoE4 . Among these isoforms, ApoE4 represents the strongest genetic risk factor for late-onset AD, increasing the risk of AD and reducing the age of AD onset , whereas ApoE3 improves synaptic plasticity and exerts a neuroprotective effect . Although the role of ApoE in AD is not yet completely understood, ApoE has been reported to repair and regenerate the neuronal membrane , suppress the onset of Aβ deposition , and exert anti-inflammatory effects . In particular, ApoE has recently been shown to carry a large number of lipids, and lipid-enriched ApoE promotes Aβ degradation and removal . The ability of ApoE to remove Aβ depends on its isoforms and its lipidation status . ABCA1 and ABCG1 are the most important ApoE-lipidating proteins, and ABCA1 mediates cholesterol transport to lipid-free apolipoproteins to produce nascent lipoproteins . Partial lipidation of ApoE inhibits its interaction with ABCA1 ; therefore, ABCG1, but not ABCA1, further induces cholesterol efflux into nascent lipoproteins to form mature lipoproteins . In fact, the absence of ABCA1 in transgenic mice increases the number of Aβ plaques by reducing the level of lipidated ApoE [30,37,38]. The esterification state of ApoE is key to its ability to clear Aβ. OAB-14 treatment increased ABCA1 and ApoE expression at 200 mg/kg, and ABCG1 expression at 100 and 200 mg/kg. However, interestingly, we were not able to repeat the results reported by Landreth and colleagues  that ABCA1 expression increased after 15 days of bexarotene treatment. Both OAB-14 and bexarotene treatments increased the levels of lipidated ApoE, which likely resulted from increased levels of ABCA1 and ABCG1. Lipidated ApoE and soluble Aβ combine to form the ApoE:Aβ complex, which was more susceptible to phagocytosis by microglia than ApoE-free Aβ . Based on our results, the clearance of soluble Aβ by OAB-14 may be related to its ability to increase the levels of esterified ApoE. Additionally, we also found that OAB-14 increased NEP and IDE expression. The two enzymes also possibly contribute to the increased Aβ clearance induced by OAB-14 treatment. Interestingly, the capacity of IDE to degrade Aβ is also governed by the lipidation status of ApoE .