Cerebrovascular deposition of amyloid-beta (Abeta) is a pathological hallmark of Alzheimer's Disease (AD). Abeta is neurotoxic and mutations within Abeta primarily manifest as cerebrovascular beta-amyloidoses, for example Dutch and Iowa type. Abeta within the intravascular space is linked to Abeta deposited in the brain and Abetatransport between the CNS, blood and cerebrospinal fluid, and across the blood-brain barrier (BBB), regulates brain Abeta. At the BBB, LRP-1 (Low-density Lipoprotein Receptor-Related Protein 1) and RAGE (Receptor for Advanced Glycation Endproducts) transport Abeta out and into the CNS, respectively. RAGE mediates Abeta suppression of cerebral blood flow, neurovascular stress and development of cerebral beta-amyloidosis. Treatment of Tg PD hAPP mice with soluble RAGE (sRAGE) decreases the CNS amyloid load and Abeta levels, and increases Abeta40/42 in plasma. Our pilot data provide evidence for a direct LRP-1/Abeta interaction and demonstrate this interaction regulates Abeta clearance. We show high affinity binding of Abeta40 to LRP-1, but greatly reduced binding of Abeta42 and mutant Abeta, by surface plasmon resonance analysis. LRP-1-mediated brain capillary uptake of Abeta and transcytosis across the mouse BBB in vivo required RAP gene and were vastly diminished by the high beta-sheet content in A(, loss of negative charges caused by Dutch/Iowa Abeta mutations and reduced LRP-1 BBB activity/expression. Transgenic APP SwDI mice producing Dutch/Iowa A( with high content of beta-sheets/low LRP-1 clearance develop amyloid/Abeta-pathology much earlier than Tg-2576 mice, despite 24-fold lower neuronal levels of human APP. RAGE null mice do not transport circulating Abeta40 into the CNS. Transport of wild-type and Dutch/Iowa Abeta40 into the CNS is accelerated in Tg-2576 mice and APP SwDI mice consistent with high expression of RAGE at the BBB. Transgenic Tie-2 LRP-1 mice express human LRP-1 transgene in brain endothelium at functionally high enough levels. We hypothesize that LRP-1 and RAGE can be manipulated at the BBB to control beta-amyloidosis in mouse models relevant to AD and familial beta-amyloidoses. We will study clearance from the CNS, transport across the BBB and the effects on cerebral blood flow and neurovascular stress of wild type and mutant Abeta40 and 42 in controls, APP SwDI, Tg-2576, Tie-2-LRP-1 and RAGE null mice (aim 1), the effects of human LRP-1 transgene at the BBB (aim 2) and deletion of RAGE gene (aim 3) on pathology in Tg-2576 and APP SwDI mice, and the effects of treatment with sRAGE and sLRP-1 fragments in Tg-2576 and APP SwDI mice (aim 4). These studies will provide new therapeutic insights to lower Abeta and prevent development of beta-amyloidosis in AD and familial Abeta-disorders by controlling Abeta CNS transport pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG023084-03
Application #
7112238
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Petanceska, Suzana
Project Start
2004-09-15
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$442,293
Indirect Cost
Name
University of Rochester
Department
Neurosurgery
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Winkler, Ethan A; Sengillo, Jesse D; Sagare, Abhay P et al. (2014) Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A 111:E1035-42
Zhao, Zhen; Zlokovic, Berislav V (2014) Blood-brain barrier: a dual life of MFSD2A? Neuron 82:728-30
Sagare, Abhay P; Bell, Robert D; Zlokovic, Berislav V (2013) Neurovascular defects and faulty amyloid-* vascular clearance in Alzheimer's disease. J Alzheimers Dis 33 Suppl 1:S87-100
Sagare, Abhay P; Bell, Robert D; Srivastava, Alaka et al. (2013) A lipoprotein receptor cluster IV mutant preferentially binds amyloid-* and regulates its clearance from the mouse brain. J Biol Chem 288:15154-66
Sengillo, Jesse D; Winkler, Ethan A; Walker, Corey T et al. (2013) Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease. Brain Pathol 23:303-10
Halliday, Matthew R; Pomara, Nunzio; Sagare, Abhay P et al. (2013) Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. JAMA Neurol 70:1198-200
Deane, Rashid; Singh, Itender; Sagare, Abhay P et al. (2012) A multimodal RAGE-specific inhibitor reduces amyloid *-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 122:1377-92
Zlokovic, Berislav V (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 12:723-38
Sagare, Abhay P; Deane, Rashid; Zetterberg, Henrik et al. (2011) Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-* is an early biomarker for mild cognitive impairment preceding Alzheimer's disease. J Alzheimers Dis 24:25-34
Winkler, Ethan A; Bell, Robert D; Zlokovic, Berislav V (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14:1398-405

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