The Role of the Cell Surface LRP and Soluble LRP in Blood-Brain Barrier Aβ Clearance in Alzheimers Disease

Abstract

Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid beta-peptide (Abeta) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty Abeta clearance from the brain appears to mediate focal Abeta accumulations in AD. Central and peripheral production of Abeta from Abeta-precursor protein (APP), transport of peripheral Abeta into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Abeta degradation, Abeta oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Abeta elimination from brain across the BBB by cell surface LRP; all may control brain Abeta levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Abeta, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Abeta binding to sLRP in plasma. This, in turn, may increase Abeta brain levels through a decreased efflux of brain Abeta at the BBB and/or reduced sequestration of plasma Abeta associated with re-entry of free Abeta into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Abeta "sink" activity of sLRP, hold potential to control brain Abeta accumulations, neuroinflammation and cerebral blood flow reductions in AD.