Cerebrovascular deposition of amyloid-13 (AI3) is a pathological hallmark of Alzheimer's Disease (AD). AI3 is neurotoxic and mutations within AI3 primarily manifest as cerebrovascular 13-amyloidoses, for example Dutch and Iowa type. AI3 within the intravascular space is linked to AI3 deposited in the brain and AI3 transport between the CNS, blood and cerebrospinal fluid, and across the blood-brain barrier (BBB), regulates brain AI3. At the BBB, LRP-1 (Low-density Lipoprotein Receptor-Related Protein 1) and RAGE (Receptor for Advanced Glycation Endproducts) transport AI3 out and into the CNS, respectively. RAGE mediates AI3 suppression of cerebral blood flow, neurovascular stress and development of cerebral 13-amyloidosis. Treatment of Tg PD hAPP mice with soluble RAGE (sRAGE) decreases the CNS amyloid load and AI3 levels, and increases AI340/42 in plasma. Our pilot data provide evidence for a direct LRP-1/AI3 interaction and demonstrate this interaction regulates AI3 clearance. We show high affinity binding of Ap40 to LRP-1, but greatly reduced binding of Ap42 and mutant AI3, by surface plasmon resonance analysis. LRP-1- mediated brain capillary uptake of AI3 and transcytosis across the mouse BBB in vivo required RAP gene and were vastly diminished by the high I_-sheet content in AI3, loss of negative charges caused by Dutch/Iowa AI3 mutations and reduced LRP-1 BBB activity/expression. Transgenic APP SwDI mice producing Dutch/Iowa Ap with high content of 13-sheets/low LRP-1 clearance develop amyloid/AI3-pathology much earlier than Tg-2576 mice, despite 24-fold lower neuronal levels of human APP. RAGE null mice do not transport circulating AI340 into the CNS. Transport of wild-type and Dutch/Iowa AI340 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 p- amyloidosis in mouse models relevant to AD and familial p-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 Ap40 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 AI3 and prevent development of _-amyloidosis in AD and familial AI3-disorders by controlling AI3 CNS transport pathways.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
Montagne, Axel; Nation, Daniel A; Pa, Judy et al. (2016) Brain imaging of neurovascular dysfunction in Alzheimer's disease. Acta Neuropathol 131:687-707
Halliday, Matthew R; Rege, Sanket V; Ma, Qingyi et al. (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab 36:216-27
Zhao, Zhen; Sagare, Abhay P; Ma, Qingyi et al. (2015) Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat Neurosci 18:978-87
Winkler, Ethan A; Nishida, Yoichiro; Sagare, Abhay P et al. (2015) GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci 18:521-30
Montagne, Axel; Pa, Judy; Zlokovic, Berislav V (2015) Vascular plasticity and cognition during normal aging and dementia. JAMA Neurol 72:495-6
Barnes, Samuel R; Ng, Thomas S C; Santa-Maria, Naomi et al. (2015) ROCKETSHIP: a flexible and modular software tool for the planning, processing and analysis of dynamic MRI studies. BMC Med Imaging 15:19
Montagne, Axel; Barnes, Samuel R; Sweeney, Melanie D et al. (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85:296-302
Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V (2015) Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease. J Cereb Blood Flow Metab 35:1055-68
Zhao, Zhen; Zlokovic, Berislav V (2014) Blood-brain barrier: a dual life of MFSD2A? Neuron 82:728-30
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

Showing the most recent 10 out of 48 publications