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O5‐06‐02: OPTIMIZATION OF TISSUE‐SELECTIVE ABCA1 AGONISTS (TSAAGS) AS AN EFFECTIVE AND TOLERATED THERAPY FOR ALZHEIMER'S DISEASE
Author(s) -
Ben Aissa Manel,
Lee Sue H.,
Lewandowski Cutler T.,
LaDu Mary Jo,
Thatcher Gregory R.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.3026
Subject(s) - abca1 , apolipoprotein e , lipid anchored protein , dementia , medicine , cholesterol , liver x receptor , pharmacology , disease , endocrinology , apolipoprotein a1 , bioinformatics , apolipoprotein b , biology , biochemistry , gene , transporter , autophagy , transcription factor , apoptosis , nuclear receptor
Background:Alzheimer’s disease and related dementia (ADRD) is a multifactorial disease presenting a challenge to drug discovery. The greatest known risk factor is the APOE4-allele with 50% and 90% risk factors for heterozygotes and homozygotes, respectively. In the brain, ABCA1 initiates the assembly of apolipoprotein E (ApoE) containing lipoprotein-particles that transport lipids throughout the CNS. ApoE4 particles are less stable and poorly lipidated, contributing to loss of function in AD, which can be mitigated by ABCA1 overexpression. One amyloid-b (Ab) related mechanism relevant to APOE4 carriers is reduced clearance of Ab. Whereas therapeutic approaches solely targeting amyloid-b (Ab) have failed in the clinic, there remains a lack of therapeutic strategies incorporating the APOE4 risk factor. We propose to restore ApoE function by promoting its lipidation using an effective and well-tolerated tissue-selective ABCA1 agonist (TSAAg), addressing the multifactorial nature of ADRD, and effective in APOE4 carriers. Methods: Previous approaches to enhance apoE function using RXR/LXR agonists, ameliorated AD-related pathology in some mouse models, but induced detrimental lipogenic activation. Therefore, we have taken an innovative functional approach to restore the function of ApoE by screening for TSAAgs, that elevate ABCA1 in astrocytes and counter-screen against SREBP1c activation in hepatocytes to mitigate against detrimental lipogenic gene activation. Screening conditions have been optimized for Z’-factors > 0.8. Selected hits with neutral lipogenic actions were further profiled based upon multifactorial properties for cholesterol metabolism; anti-inflammatory, and insulin-sensitizing effects. Toxicodynamic and pharmacodynamics (TD/PD) studies were performed in WT, high-fat-diet-fed mice and in an AD-model. Results: From initial 25,000-compounds, 5 Chemotypes were selected for SAR and probed in primary astrocytes for regulation of cholesterol efflux and genes associated with neuroinflammation, energy utilization, insulin sensitivity, and cholesterol metabolism. Using liver, plasma, and brain biomarkers, TD/PD data and target-engagement were validated in vivo, compatible with in vitro data. Remarkably, in both mouse models, oral administration of TSAAg reversed cognitive deficits. Conclusions:A Preclinical Proof-Of-Concept was established. We propose that this functional approach has potential to impact multiple factors that contribute to ADRD, both associated with and not directly associated with Ab, in the highly vulnerable APOE4 population.