RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease

Abstract

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.

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

“…The major features of RAGE activation in contributing to AD result from its interaction with A␤. RAGE interaction with A␤ results in perturbation of neuronal function, amplification of glial inflammatory response, elevation of oxidative stress and amyloidosis, and increased A␤ influx at the BBB (75)(76)(77)(78). Our results suggest that A␤-RAGE interaction at the BBB links the intracerebral A␤ deposition to systemic immune T cells by up-regulating CCR5 on brain endothelial cells.…”

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…Receptor for advanced glycation end products (RAGE) has been suggested to transport Aβ across the BBB, from the blood into the brain 38 . Expression of the AGER gene (encoding RAGE) is upregulated in the AD brain vasculature 39,40 , indicating that influx of peripheral Aβ into the brain is increased in AD. The contribution of peripherally derived Aβ to amyloidosis in the AD brain needs to be determined in future studies.…”

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

“…2,16 Incidentally, an upregulation of RAGE and a downregulation of LRP1 were shown in the AD brain where both changes could contribute to the accumulation and deposition of Aβ. 17,18 However, recent data suggest that APOE4 expression exerts detrimental effects on the cerebrovascular system including BBB impairments. 10 Indeed, human apoE4 expression in the mouse, compared with apoE2 and apoE3, results in altered BBB permeability and reduced cerebral blood flow.…”