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On Alzheimer's Amyloid ß Peptide Transport at the Blood-Brain barrier

Submitter: Berislav V. Zlokovic 1,2, Thomas Wisniewski3, Lary C. Walker4, Jorge Ghiso3 and Blas Frangione3 | zlokovic@hsc.usc.edu

1Neurosurg.2Physiol., USC Sch. Med., 3 Pathol., NYU Med. Cntr., 4Neurosci. Ther., Parke- Davis

Published December 1, 1998

This article elegantly demonstrates that the monoclonal antibody against the blood-brain barrier (BBB) insulin receptor can be utilized as a piggy-back ride to deliver Alzheimer's amyloid ß peptide (Aß) to the brain of adult Rhesus monkey.(1) However, other plausible mechanisms for Aß interactions with different BBB receptors and/or binding proteins that all may significantly influence its transport within the central nervous system (CNS) are not discussed.
Recent studies with Aß1-40, Aß1-42 and AßQ22 (the Dutch mutant) indicated that specific mechanisms at the BBB play a major role in regulating Aß concentrations in cerebral vasculature and brain.(2) Circulating Aß may increase the level of soluble Aß in the CNS(3- 5)followed by deposition onto pre-existing vascular amyloid lesions in non -human primates.(6,7) Two specific cell- surface acceptor sites for Aß on brain endothelial cells, i.e., the receptor for advanced glycation end products (RAGE)(8) and class A scavenger receptor (SR),(9) participate in binding and internalization of free Aß at the BBB, while RAGE is involved in transcytosis of Aß1-40 across human BBB in vitro.(10) The gp330/megalin and possibly other members of the low density lipoprotein receptor family, i.e., LRP-1, LDLR and VLDLR, participate in brain microvascular accumulation and transfer of blood-borne Aß complexed with apolipoproteins J and E4 (apoJ, apoE4) delipidated and/or incorporated into lipoprotein particles.(11,12) The BBB permeability to Aß-apoJ via gp330/megalin was high,(11) and transport saturable at physiological plasma levels of apoJ.(13) RAGE, SR and several adhesion molecules mediate brain endothelial damage by free Aß.(8,9,14,15)
Brain capillary binding and specific Aß transport are enhanced in aged squirrel monkey with cerebral amyloid angiopathy (CAA)(7), and in an in vitro model of the BBB from AD patients.(16) Aged Rhesus monkeys do not frequently develop CAA, but have extensive parenchymal Aß deposits.(17) The concentration of Aß in the CNS and cerebral vasculature increases with age and may reach the neurotoxic level with concomitant development of the disease process such as AD.(18) In the CNS of healthy young individuals, the metabolism of Aß in brain and rapid clearance from the cerebrospinal fluid may counteract the BBB transport.(19) However, the aging process and the risk factors for AD (e.g., presenilin genes, apoE4 genotype, etc.) may affect trafficking of Aß in the CNS and at the BBB with an impact on the development of cerebral amyloidosis and AD pathology.(20)
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