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ApoE-directed therapeutics rapidly clear ?-amyloid and reverse deficits in AD mouse models.

ABSTRACT: Alzheimer's disease (AD) is associated with impaired clearance of ?-amyloid (A?) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble A? within hours in an apoE-dependent manner. A? plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological A? clearance mechanisms, resulting in the rapid reversal of a broad range of A?-induced deficits.

SUBMITTER: Cramer PE

PROVIDER: S-EPMC3651582 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.

Cramer Paige E PE Cirrito John R JR Wesson Daniel W DW Lee C Y Daniel CY Karlo J Colleen JC Zinn Adriana E AE Casali Brad T BT Restivo Jessica L JL Goebel Whitney D WD James Michael J MJ Brunden Kurt R KR Wilson Donald A DA Landreth Gary E GE

Science (New York, N.Y.) 20120209 6075

Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in ...[more]

PMID: 22323736

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Project description:AimStreptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice.MethodsCell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains.ResultsLX2343 (5-20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aβ pathology in their brains.ConclusionLX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aβ production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.

Dataset Information

ApoE-directed therapeutics rapidly clear ?-amyloid and reverse deficits in AD mouse models.

Publications

ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.

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