RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease.
The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of beta-amyloid across the blood-brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of beta-amyloid out of the brain. To determine whether there are Alzheimer's disease (AD)-related changes in these BBB-associated beta-amyloid receptors, we studied RAGE, LRP-1, and beta-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and beta-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and beta-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.
Donahue
John E
JE
Department of Clinical Neurosciences, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA. JDonahue3@Lifespan.org
Flaherty
Stephanie L
SL
Johanson
Conrad E
CE
Duncan
John A
JA
Silverberg
Gerald D
GD
Miller
Miles C
MC
Tavares
Rosemarie
R
Yang
Wentian
W
Wu
Qian
Q
Sabo
Edmond
E
Hovanesian
Virginia
V
Stopa
Edward G
EG
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism
D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D026503:Low Density Lipoprotein Receptor-Related Protein-1