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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-CNBT (01))
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Petanceska, Suzana
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University of Rochester
Schools of Dentistry
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