The role of the cell surface LRP and soluble LRP in blood-brain barrier a clearance in Alzheimer's Disease

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