Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease

Journal of Cerebral Blood Flow and Metabolism

Volumn 37, Issue 1, 2017, Pages 217-226

  Lin, Ai Ling ^a,b   Jahrling, Jordan B ^c   Zhang, Wei ^c   Derosa, Nicholas ^c   Bakshi, Vikas ^a   Romero, Peter ^c   Galvan, Veronica ^c   Richardson, Arlan ^d  

^a UNIVERSITY OF KENTUCKY   (United States)

^b UNIVERSITY OF KENTUCKY   (United States)

^c UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^d UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER   (United States)

Author keywords

Alzheimer's disease; APOE4; blood brain barrier; Brain imaging; cerebral blood flow; cerebral glucose metabolism; cognition; inflammation; rapamycin

Indexed keywords

APOLIPOPROTEIN E4; CYCLOPHILIN A; GLUCOSE; RAPAMYCIN;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ASYMPTOMATIC DISEASE; BLOOD BRAIN BARRIER; BODY WEIGHT; BRAIN BLOOD FLOW; CLINICAL OUTCOME; CONTROLLED STUDY; DISEASE COURSE; FEMALE; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; HIPPOCAMPUS; IN VIVO STUDY; LEARNING DISORDER; METABOLIC DISORDER; MOUSE; NEUROIMAGING; NONHUMAN; PRIORITY JOURNAL; TEMPORAL LOBE; VASCULAR DISEASE; ANIMAL; BRAIN CIRCULATION; COMPLICATION; DRUG EFFECTS; GENETICS; GLUCOSE METABOLISM DISORDERS; LEARNING DISORDERS; METABOLIC DISEASES; PATHOLOGY; PROCEDURES; SECONDARY PREVENTION; TRANSGENIC MOUSE; TRENDS; VASCULAR DISEASES;

ALZHEIMER DISEASE; ANIMALS; APOLIPOPROTEIN E4; BLOOD-BRAIN BARRIER; CEREBROVASCULAR CIRCULATION; GLUCOSE METABOLISM DISORDERS; LEARNING DISORDERS; METABOLIC DISEASES; MICE; MICE, TRANSGENIC; NEUROIMAGING; SECONDARY PREVENTION; SIROLIMUS; VASCULAR DISEASES;

EID: 85006512188     PISSN: 0271678X     EISSN: 15597016     Source Type: Journal    
DOI: 10.1177/0271678X15621575     Document Type: Article

References (48)

1. Liu CC, Kanekiyo T, Xu H, et al. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Rev Neurol 2013; 9: 106-118.
2. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921-923.
3. Thambisetty M, Beason-Held L, An Y, et al. APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol 2010; 67: 93-98.
4. Reiman EM, Chen K, Alexander GE, et al. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci USA 2005; 102: 8299-8302.
5. Reiman EM, Caselli RJ, Chen K, et al. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci USA 2001; 98: 3334-3339.
6. Fleisher AS, Chen K, Liu X, et al. Apolipoprotein E epsilon4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging 2013; 34: 1-12.
7. Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci USA 2004; 101: 284-289.
8. Bell RD, Winkler EA, Singh I, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 2012; 485: 512-516.
9. Austin BP, Nair VA, Meier TB, et al. Effects of hypoper-fusion in Alzheimer's disease. J Alzheimer's Dis 2011; 26(Suppl 3): 123-133.
10. Zlokovic BV. Neurovascular pathways to neurodegenera-tion in Alzheimer's disease and other disorders. Nature Rev Neurosci 2011; 12: 723-738.
11. Alata W, Ye Y, St-Amour I, et al. Human apolipoprotein E varepsilon4 expression impairs cerebral vascularization and blood-brain barrier function in mice. J Cereb Blood Flow Metab 2015; 35: 86-94.
12. Lin AL, Zheng W, Halloran JJ, et al. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb Blood Flow Metab 2013; 33: 1412-1421.
13. Spilman P, Podlutskaya N, Hart MJ, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PloS One 2010; 5: e9979.
14. Mielke MM, Vemuri P and Rocca WA. Clinical epidemiology of Alzheimer's disease: assessing sex and gender differences. Clin Epidemiol 2014; 6: 37-48.
15. Kilkenny C, Browne W, Cuthill IC, et al. Animal research: reporting in vivo experiments-the ARRIVE guidelines. J Cereb Blood Flow Metab 2011; 31: 991-993.
16. Zlokovic BV. Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol 2013; 70: 440-444.
17. Salomon-Zimri S, Boehm-Cagan A, Liraz O, et al. Hippocampus-related cognitive impairments in Young apoE4 targeted replacement mice. Neurodegener Dis 2014; 13: 86-92.
18. Yin JX, Turner GH, Lin HJ, et al. Deficits in spatial learning and memory is associated with hippocampal volume loss in aged apolipoprotein E4 mice. J Alzheimer's Dis 2011; 27: 89-98.
19. Pulliam DA, Deepa SS, Liu Y, et al. Complex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses. Biochem J 2014; 462: 359-371.
20. Liu Y, Diaz V, Fernandez E, et al. Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging 2014; 6: 742-754.
21. Galvan V, Gorostiza OF, Banwait S, et al. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci USA 2006; 103: 7130-7135.
22. Brommelhoff JA and Sultzer DL. Brain structure and function related to depression in Alzheimer's disease: contributions from neuroimaging research. J Alzheimer's Dis 2015; 45: 689-703.
23. Kehoe EG, McNulty JP, Mullins PG, et al. Advances in MRI biomarkers for the diagnosis of Alzheimer's disease. Biomarker Med 2014; 8: 1151-1169.
24. Lin AL, Zhang W, Gao X, et al. Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain. Neurobiol Aging 2015; 36: 2296-2303.
25. Eichenbaum H. Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 2004; 44: 109-120.
26. Halliday MR, Rege SV, Ma Q, et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apo-lipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. Epub ahead of print 11 March 2015. DOI: 10.1038/jcbfm.2015.44.
27. Steiner JP, Connolly MA, Valentine HL, et al. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. Nat Med 1997; 3: 421-428.
28. Fox PT, Raichle ME, Mintun MA, et al. Nonoxidative glucose consumption during focal physiologic neural activity. Science 1988; 241: 462-464.
29. Lin AL, Gao JH, Duong TQ, et al. Functional neuroima-ging: a physiological perspective. Front Neuroenergetics 2010; 2: 1-5.
30. Lin AL, Fox PT, Hardies J, et al. Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex. Proc Natl Acad Sci USA 2010; 107: 8446-8451.
31. Lin AL, Coman D, Jiang L, et al. Caloric restriction impedes age-related decline of mitochondrial function and neuronal activity. J Cereb Blood Flow Metab 2014; 34: 1440-1443.
32. Dash PK, Orsi SA and Moore AN. Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex-Mammalian target of rapamycin pathway. J Neurosci 2006; 26: 8048-8056.
33. Poels MM, Ikram MA, Vernooij MW, et al. Total cerebral blood flow in relation to cognitive function: the Rotterdam Scan Study. J Cereb Blood Flow Metab 2008; 28: 1652-1655.
34. Cunnane S, Nugent S, Roy M, et al. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition 2011; 27: 3-20.
35. Nagata K, Buchan RJ, Yokoyama E, et al. Misery per-fusion with preserved vascular reactivity in Alzheimer's disease. Ann N Y Acad Sci 1997; 826: 272-281.
36. Nagata K, Kondoh Y, Atchison R, et al. Vascular and metabolic reserve in Alzheimer's disease. Neurobiol Aging 2000; 21: 301-307.
37. Stranahan AM and Mattson MP. Metabolic reserve as a determinant of cognitive aging. J Alzheimer's Dis 2012; 30(Suppl 2): S5-S13.
38. Lin AL, Pulliam DA, Deepa SS, et al. Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice. J Cereb Blood Flow Metab 2013; 33: 1605-1611.
39. Youmans KL, Tai LM, Nwabuisi-Heath E, et al. APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 2012; 287: 41774-41786.
40. Lin AL, Laird AR, Fox PT, et al. Multimodal MRI neu-roimaging biomarkers for cognitive normal adults, amnestic mild cognitive impairment, and Alzheimer's dis-ease. Neurol Res Int 2012; 2012: 907409.
41. Lin AL and Rothman DL. What have novel imaging techniques revealed about metabolism in the aging brain? Future Neurol 2014; 9: 341-354.
42. Uh J, Lin AL, Lee K, et al. Validation of VASO cerebral blood volume measurement with positron emission tomography. Magn Reson Med 2011; 65: 744-749.
43. Soefje SA, Karnad A and Brenner AJ. Common toxicities of mammalian target of rapamycin inhibitors. Target Oncol 2011; 6: 125-129.
44. Hurez V, Dao V, Liu A, et al. Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice. Aging Cell. Epub ahead of print 28 August 2015. DOI: 10.1111/acel.12380.
45. Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, et al. mTOR inhibition improves immune function in the elderly. Science translational medicine 2014; 6(268): 268ra179.
46. Alvarado Y, Mita MM, Vemulapalli S, et al. Clinical activity of mammalian target of rapamycin inhibitors in solid tumors. Target Oncol 2011; 6: 69-94.
47. Mita MM, Mita A and Rowinsky EK. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Therapy 2003; 2(4 Suppl 1): S169-S177.
48. Richardson A, Galvan V, Lin AL, et al. How longevity research can lead to therapies for Alzheimer's disease: the rapamycin story. Exp Gerontol 2014; 68: 51-58.