Amyloid efflux transporter expression at the blood-brain barrier declines in normal aging.
Reduced clearance of amyloid β peptides (Aβ) across the blood-brain barrier contributes to amyloid accumulation in Alzheimer disease. Amyloid β efflux transport is via the endothelial low-density lipoprotein receptor-related protein 1 (LRP-1) and P-glycoprotein (P-gp), whereas Aβ influx transport is via the receptor for advanced glycation end products. Because age is the major risk factor for developing Alzheimer disease, we measured LRP-1 and P-gp expression and associated transporter expression with Aβ accumulation in aging rats. Quantitative LRP-1 and P-gp microvessel expression was measured by immunohistochemistry (IHC); LRP-1 and P-gp expression were assessed in microvessel isolates by Western blotting. There was an age-dependent loss of capillary LRP-1 across all ages (3-36 months) by IHC (linear trend p = 0.0004) and between 3 and 20 months by Western blotting (linear trend p < 0.0001). There was a late (30-36 months) P-gp expression loss by IHC (p < 0.05) and Western blotting (p = 0.0112). Loss of LRP-1 correlated with Aβ42 accumulation (p = 0.0121) and very nearly with Aβ40 (p = 0.0599) across all ages. Expression of LRP-1 correlated negatively with the expression of receptor for advanced glycation end products (p < 0.0004). These data indicate that alterations in LRP-1 and P-gp expression seem to contribute progressively to Aβ accumulation in aging.
Silverberg
Gerald D
GD
Department of Neurosurgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA. geralds@stanford.edu
Messier
Arthur A
AA
Miller
Miles C
MC
Machan
Jason T
JT
Majmudar
Samir S
SS
Stopa
Edward G
EG
Donahue
John E
JE
Johanson
Conrad E
CE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D018916:Blood-Aqueous Barrier / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D016014:Linear Models; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000682:Amyloid; D016229:Amyloid beta-Peptides; D026901:Membrane Transport Proteins; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C051223:peptidoglycan receptor