APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease

NEUROBIOLOGY OF DISEASE

卷:139

Review

Lin, Ai-Ling^1,2,3,4  Parikh, Ishita^1,5  Yanckello, Lucille M.^1,2  White, Renee S.^1,6  Hartz, Anika M. S.^1,2  Taylor, Chase E.¹  McCulloch, Scott D.⁷  Thalman, Scott W.^1,4  Xia, Mengfan²  McCarty, Katie¹  Ubele, Margo¹  Head, Elizabeth^8,9  Hyder, Fahmeed^10,11,12,13  Sanganahalli, Basavaraju G.^10,11,12,13 

[1] Univ Kentucky, Sanders Brown Ctr Aging, 800 S Limestone St, Lexington, KY 40536 USA

[2] Univ Kentucky, Dept Pharmacol & Nutr Sci, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Neurosci, Lexington, KY 40536 USA

[4] Univ Kentucky, F Joseph Halcomb III Dept Biomed Engn, Lexington, KY 40536 USA

[5] Oklahoma Med Res Fdn, 825 NE 13th St, Oklahoma City, OK 73104 USA

[6] Georgetown Coll, Georgetown, KY USA

[7] Metabolon Inc, Durham, NC USA

[8] Univ Calif Irvine, Dept Pathol & Lab Med, Irvine, CA USA

[9] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA USA

[10] Yale Univ, Magnet Resonance Res Ctr, New Haven, CT USA

[11] Yale Univ, Quantitat Neurosci Magnet Resonance Core Ctr, New Haven, CT USA

[12] Yale Univ, Dept Diagnost Radiol, New Haven, CT 06510 USA

[13] Yale Univ, Dept Biomed Engn, New Haven, CT USA

关键词: APOE4;    APOE3;    Alzheimer's disease prevention;    Rapamycin;    mTOR;    MRI;    Pharmacogentics;    Cerebral blood flow;    Cerebrometabolic function;    White matter integrity;    Blood brain barrier;    Amyloid-beta plaques;    Cognition;    Cerebrovascular reactivity;    Water content;    Neuroinflammation;   

DOI  :  10.1016/j.nbd.2020.104834

来源: Elsevier

【 摘 要 】

The epsilon 4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid beta (A beta) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit A beta retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in the mice that express human APOE4 gene and overexpress A beta (the E4FAD mice). Another goal of the study was to identify the potential pharmacogenetic differences in response to rapamycin between the E4FAD and E3FAD mice, the mice with human APOE epsilon 3 allele. We used multi-modal MRI to measure in vivo cerebral blood flow (CBF), neurotransmitter levels, white matter integrity, water content, cerebrovascular reactivity (CVR) and somatosensory response; used behavioral assessments to determine cognitive function; used biochemistry assays to determine A beta retention and blood-brain barrier (BBB) functions; and used metabolomics to identify brain metabolic changes. We found that in the E4FAD mice, rapamycin normalized bodyweight, restored CBF (especially in female), BBB activity for A beta transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced A beta retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice. As the multi-modal MRI methods used in the study are readily to be used in humans and rapamycin is FDA-approved, our results may pave a way for future clinical testing of the pharmacogenetic responses in humans with different APOE alleles, and potentially using rapamycin to prevent AD for asymptomatic APOE4 carriers.