Amyloid β (Aβ) plaque, comprised mainly by Aβ peptides, is an important pathology of Alzheimer’s brains. Major efforts have been devoted to targeting this neurotoxic Aβ peptide for discovering disease-modifying treatments for Alzheimer’s disease. Inasmuch as Aβ is found in both the brain and the periphery, it is hypothesized that there is some form of equilibrium for the Aβ in the brain and the periphery such that Aβ can be transported across the blood-brain barrier. By modulating the periphery Aβ levels, it is predicted that the brain Aβ levels will undergo concomitant changes, forming the basis of the “sink hypothesis” for Aβ lowering strategies. In this review, the significance and implication of this sink hypothesis as well as how the sink hypothesis may contribute to the recent Aβ-based drug discovery in AD are discussed. Ultimately, the validity of the sink hypothesis will be resolved when the appropriate Aβ agents are being tested in the clinic.
Andreasen N., Minthon L., Vanmechelen E., Vanderstichele H., Davidsson P., Winblad B., and others.1999a. Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer’s disease in patients with mild cognitive impairment. Neurosci Lett273:5-8.
2.
Andreasen N., Hesse C., Davidsson P., Minthon L., Wallin A., Winblad B., and others.1999b. Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol56:673-80.
3.
Banks WA, Kastin AJ1989. Inhibition of the brain to blood transport system for enkephalins and Tyr-MIF-1 in mice addicted or genetically predisposed to drinking ethanol. Alcohol6:53-7.
4.
Banks WA, Kastin AJ, Huang W., Jaspan JB, Maness LM1996. Leptin enters the brain by a saturable system independent of insulin. Peptides17:305-11.
5.
Banks WA, Kastin AJ, Maness LM, Banks MF, Shayo M., McLay RN1997. Interactions of beta-amyloids with the blood-brain barrier . Ann N Y Acad Sci826:190-9.
6.
Bateman RJ, Munsell LY, Morris JC, Swarm R., Yarasheski KE, Holtzman DM2006. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med12:856-61.
7.
Baura GD, Foster DM, Porte D. Jr, Kahn SE, Bergman RN, Cobelli C., and others.1993. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest92:1824-30.
8.
Bayer AJ, Bullock R., Jones RW, Wilkinson D., Paterson KR, Jenkins L., and others.2005. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology64:94-101.
9.
Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R., and others.2007. Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab27:909-18.
10.
Cappai R., White AR1999. Amyloid beta. Int J Biochem Cell Biol31:885-9.
11.
Cirrito JR, Deane R., Fagan AM, Spinner ML, Parsadanian M., Finn MB, and others.2005. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model . J Clin Invest115:3285-90.
12.
Colle MA, Duyckaerts C., Laquerriere A., Pradier L., Czech C., Checler F., and others.2000. Laminar specific loss of isocortical presenilin 1 immunoreactivity in Alzheimer’s disease. Correlations with the amyloid load and the density of taupositive neurofibrillary tangles. Neuropathol Appl Neurobiol26:117-23.
13.
De Kosky ST, Scheff SW1990. Synapse loss in frontal lobe biopsies in Alzheimer’s disease: Correlation with cognitive severity. Ann Neurol27:457-64.
14.
Deane R., Zlokovic BV2007. Role of the blood-brain barrier in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res4:191-7.
15.
Deane R., Sagare A., Zlokovic BV2008. The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer’s disease. Curr Pharm Des14:1601-5.
16.
Deane R., Wu Z., Sagare A., Davis J., Du Yan S., Hamm K., and others.2004. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron43:333-44.
17.
Deane R., Yan SD, Submamaryan RK, LaRue B., Jovanovic S., Hogg E., and others.2003. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med9:907-13.
18.
DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM2002. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science295:2264-7.
19.
Donahue JE, Flaherty SL, Johanson CE, Duncan JA 3rd, Silverberg GD, Miller MC, and others.2006. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol112:405-15.
20.
Fernandez-Gamba A., Leal MC, Morelli L., Castano EM2009. Insulin-degrading enzyme: structure-function relationship and its possible roles in health and disease. Curr Pharm Des15:3644-55.
21.
Gearing M., Schneider JA, Robbins RS, Hollister RD, Mori H., Games D., and others.1995. Regional variation in the distribution of apolipoprotein E and A beta in Alzheimer’s disease. J Neuropathol Exp Neurol54:833-41.
22.
Ghiso J., Frangione B.2002. Amyloidosis and Alzheimer’s disease. Adv Drug Deliv Rev54:1539-51.
23.
Glenner GG, Wong CW1984. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun120:885-90.
24.
He X., Cooley K., Chung CH, Dashti N., Tang J.2007. Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production. J Neurosci27:4052-60.
25.
Herring A., Ambree O., Tomm M., Habermann H., Sachser N., Paulus W., Keyvani K.2009. Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology. Exp Neurol216:184-92.
Holtzman DM, Bales KR, Paul SM, DeMattos RB2002. Abeta immunization and anti-Abeta antibodies: potential therapies for the prevention and treatment of Alzheimer’s disease. Adv Drug Deliv Rev54:1603-13.
29.
Ida N., Hartmann T., Pantel J., Schroder J., Zerfass R., Forstl H., and others.1996. Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem271:22908-14.
30.
Kanai M., Shizuka M., Urakami K., Matsubara E., Harigaya Y., Okamoto K., and others.1999. Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer’s disease . Neurosci Lett267:65-8.
31.
Kayed R., Head E., Thompson JL, McIntire TM, Milton SC, Cotman CW, and others.2003. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science300:486-9.
32.
Kim J., Basak JM, Holtzman DM2009. The role of apolipoprotein E in Alzheimer’s disease . Neuron63:287-303.
33.
Kuentzel SL, Ali SM, Altman RA, Greenberg BD, Raub TJ1993. The Alzheimer beta-amyloid protein precursor/protease nexin-II is cleaved by secretase in a trans-Golgi secretory compartment in human neuroglioma cells. Biochem J295: 367-78.
34.
Kuo YM, Emmerling MR, Lampert HC, Hempelman SR, Kokjohn TA, Woods AS, and others.1999. High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer’s disease. Biochem Biophys Res Commun257: 787-91.
35.
Lam FC, Liu R., Lu P., Shapiro AB, Renoir JM, Sharom FJ, and others.2001. beta-Amyloid efflux mediated by p-glycoprotein . J Neurochem76:1121-8.
36.
Lauren J., Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM2009. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature457:1128-32.
37.
Lee DH, Strittmatter SM, Sah DW2003. Targeting the Nogo receptor to treat central nervous system injuries. Nat Rev Drug Discov2:872-8.
38.
Lemere CA, Maron R., Selkoe DJ, Weiner HL2001. Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer’s disease. DNA Cell Biol20:705-11.
39.
Lemere CA, Beierschmitt A., Iglesias M., Spooner ET, Bloom JK, Leverone JF, and others.2004. Alzheimer’s disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol165:283-97.
40.
Lemere CA, Lopera F., Kosik KS, Lendon CL, Ossa J., Saido TC, and others.1996. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med2:1146-50.
41.
Lesne S., Koh MT, Kotilinek L., Kayed R., Glabe CG, Yang A., and others.2006. A specific amyloid-beta protein assembly in the brain impairs memory. Nature440:352-7.
42.
Lewis J., Dickson DW, Lin WL, Chisholm L., Corral A., Jones G., and others.2001. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science293:1487-91.
43.
Li M., Chen L., Lee DH, Yu LC, Zhang Y.2007. The role of intracellular amyloid beta in Alzheimer’s disease. Prog Neurobiol83:131-9.
44.
Mann DM, Brown A., Wilks DP, Davies CA1989. Immunocytochemical and lectin histochemical studies of plaques and tangles in Down’s syndrome patients at different ages. Prog Clin Biol Res317:849-56.
45.
Martel CL, Mackic JB, Matsubara E., Governale S., Miguel C., Miao W., and others.1997. Isoform-specific effects of apolipoproteins E2, E3, and E4 on cerebral capillary sequestration and blood-brain barrier transport of circulating Alzheimer’s amyloid beta. J Neurochem69:1995-2004.
46.
Matsubara E., Ghiso J., Frangione B., Amari M., Tomidokoro Y., Ikeda Y., and others.1999. Lipoprotein-free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer’s disease and Down’s syndrome. Ann Neurol45:537-41.
47.
Motter R., Vigo-Pelfrey C., Kholodenko D., Barbour R., Johnson-Wood K., Galasko D., and others.1995. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol38:643-8.
48.
Nalivaeva NN, Fisk LR, Belyaev ND, Turner AJ2008. Amyloid-degrading enzymes as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res5:212-24.
49.
Oldendorf WH1971. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol221:1629-39.
50.
Pan W., Banks WA, Kennedy MK, Gutierrez EG, Kastin AJ1996. Differential permeability of the BBB in acute EAE: enhanced transport of TNT-alpha. Am J Physiol271:E636-42.
51.
Park JH, Strittmatter SM2007. Nogo receptor interacts with brain APP and Abeta to reduce pathologic changes in Alzheimer’s transgenic mice. Curr Alzheimer Res4:568-70.
52.
Park JH, Widi GA, Gimbel DA, Harel NY, Lee DH, Strittmatter SM2006. Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer’s transgenic mice. J Neurosci26:13279-86.
53.
Podlisny MB, Lee G., Selkoe DJ1987. Gene dosage of the amyloid beta precursor protein in Alzheimer’s disease. Science238:669-71.
54.
Price DL, Sisodia SS1998. Mutant genes in familial Alzheimer’s disease and transgenic models. Annu Rev Neurosci21: 479-505.
55.
Pride M., Seubert P., Grundman M., Hagen M., Eldridge J., Black RS2008. Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis . Neurodegener Dis5:194-96.
56.
Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R., Klunk WE, and others. 2010. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol9:363-72.
57.
Romero LI, Kakucska I., Lechan RM, Reichlin S.1996. Interleukin-6 (IL-6) is secreted from the brain after intra-cerebroventricular injection of IL-1 beta in rats. Am J Physiol270:R518-24.
58.
Sagare A., Deane R., Bell RD, Johnson B., Hamm K., Pendu R., and others.2007. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med13:1029-31.
59.
Schwartz MW, Peskind E., Raskind M., Boyko EJ, Porte D. Jr.1996. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med2:589-93.
60.
Selkoe DJ2000. Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci924:17-25.
Selkoe DJ2007. Developing preventive therapies for chronic diseases: lessons learned from Alzheimer’s disease. Nutr Rev65:S239-43.
63.
Shibata M., Yamada S., Kumar SR, Calero M., Bading J., Frangione B., and others.2000. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier . J Clin Invest106:1489-99.
64.
Shoji M., Matsubara E., Kanai M., Watanabe M., Nakamura T., Tomidokoro Y., and others.1998. Combination assay of CSF tau, A beta 1-40 and A beta 1-42(43) as a biochemical marker of Alzheimer’s disease . J Neurol Sci158:134-40.
65.
Silverberg GD, Mayo M., Saul T., Rubenstein E., McGuire D.2003. Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol2:506-11.
66.
Sinha S., Lieberburg I.1999. Cellular mechanisms of beta-amyloid production and secretion . Proc Natl Acad Sci U S A96:11049-53.
67.
Smith MJ, Kwok JB, McLean CA, Kril JJ, Broe GA, Nicholson GA, and others.2001. Variable phenotype of Alzheimer’s disease with spastic paraparesis. Ann Neurol49:125-9.
68.
Stern DM, Yan SD, Yan SF, Schmidt AM2002. Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev1:1-15.
69.
Tamaki C., Ohtsuki S., Iwatsubo T., Hashimoto T., Yamada K., Yabuki C., and others.2006. Major involvement of low-density lipoprotein receptor-related protein 1 in the clearance of plasma free amyloid beta-peptide by the liver. Pharm Res23:1407-16.
70.
Tamaoka A., Fukushima T., Sawamura N., Ishikawa K., Oguni E., Komatsuzaki Y., and others.1996. Amyloid beta protein in plasma from patients with sporadic Alzheimer’s disease. J Neurol Sci141:65-8.
71.
Tang BL, Liou YC2007. Novel modulators of amyloid-beta precursor protein processing . J Neurochem100:314-23.
72.
Tanzi RE, Moir RD, Wagner SL2004. Clearance of Alzheimer’s Abeta peptide: the many roads to perdition. Neuron43:605-8.
73.
Terry RD, Masliah E., Salmon DP1991. Physical basis of cognitive alterations in Alzheimer’s disease: synaptic loss is a major correlate of cognitive impairment. Ann Neurol30:572-80.
74.
Tsai J., Grutzendler J., Duff K., Gan WB2004. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci7: 1181-3.
75.
Van Uden E., Mallory M., Veinbergs I., Alford M., Rockenstein E., Masliah E.2002. Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein. J Neurosci22:9298-304.
76.
von Arnim CA, Kinoshita A., Peltan ID, Tangredi MM, Herl L., Lee BM, and others.2005. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem280:17777-85.
77.
Wang DS, Dickson DW, Malter JS2006. beta-Amyloid degradation and Alzheimer’s disease . J Biomed Biotechnol2006: 58406.
78.
Weller RO, Subash M., Preston SD, Mazanti I., Carare RO2008. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol18: 253-66.
79.
Weller RO, Preston SD, Subash M., Carare RO2009. Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer’s disease. Alzheimers Res Ther1:6.
80.
Wilcock GK 2010. Bapineuzumab in Alzheimer’s disease: where now?Lancet Neurol9:134-6.
81.
Wisniewski T., Boutajangout A., 2010. Immunotherapeutic approaches for Alzheimer’s disease in transgenic mouse models. Brain Struct Funct214:201-18.
82.
Yan SD, Zhu H., Zhu A., Golabek A., Du H., Roher A., and others.2000. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med6:643-51.
83.
Yan SD, Chen X., Fu J., Chen M., Zhu H., Roher A., and others.1996. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature382:685-91.
84.
Ye S., Huang Y., Mullendorff K., Dong L., Giedt G., Meng EC, and others.2005. Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proc Natl Acad Sci U S A102:18700-5.
85.
Zhang Y., McLaughlin R., Goodyer C., LeBlanc A.2002. Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol156:519-29.
86.
Zlokovic BV2008. New therapeutic targets in the neurovascular pathway in Alzheimer’s disease. Neurotherapeutics5: 409-14.
87.
Zlokovic BV, Mackic JB, Djuricic B., Davson H.1989. Kinetic analysis of leucine-enkephalin cellular uptake at the luminal side of the blood-brain barrier of an in situ perfused guinea-pig brain. J Neurochem53:1333-40.
88.
Zlokovic BV, Hyman S., McComb JG, Lipovac MN, Tang G., Davson H.1990. Kinetics of arginine-vasopressin uptake at the blood-brain barrier. Biochim Biophys Acta1025: 191-8.
89.
Zlokovic BV, Martel CL, Matsubara E., McComb JG, Zheng G., McCluskey RT, and others.1996. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci U S A93:4229-34.
