Immunohistochemical Detection of Receptor-Associated Protein in Normal Human Brain and Alzheimer's Disease

This study is one of the few to characterize immunohistochemically the distribution and localization of Receptor-Associated Protein (RAP) in human autopsy brain. The results show prominent cortical neuronal localization. RAP is clearly identified in large neuronal dendritic/axonal processes. RAP is expressed in both large pyramidal and smaller interneurons. Occasional, much less frequent RAP is detectable in glial cells in white matter, which appear to be predominantly astrocytic. Although RAP is detectable immunohistochemically in Alzheimer's disease autopsy brain, the level of expression appears significantly reduced relative to age-matched control brains. These results suggest, at the immunohistochemical level, that there is a reduction of RAP protein in Alzheimer's disease brain (cortex). In terms of Alzheimer's disease pathophysiology, a reduction of neuronal RAP could then lead to reduced membrane expression of LRP, since RAP has also been shown to be an LRP antagonist. 1. Introduction Receptor-associated protein (RAP) is a 39-kilo Dalton protein which is part of the large family of small GTPase proteins. It has also been shown to be a molecular chaperone for a number of receptor proteins, including low density lipoprotein receptor-related protein (LRP) [1–4]. LRP is a membrane protein which binds to amyloid precursor protein (APP), allowing its uptake and cellular internalization and subsequent processing to beta amyloid peptides [5, 6]. Alzheimer’s disease is characterized by the excessive accumulations of beta amyloid peptide within brain regions, including areas of cortex. Beta amyloid is a peptide fragment derived from the larger precursor protein APP. The pathophysiology underlying the vast majority of Alzheimer’s disease, that is, the sporadic nonfamilial cases, remains unknown. Given that RAP can modulate LRP function; it potentially could play a role in the transmembrane intracellular handling of APP and subsequent conversion to beta amyloid peptide. This clearly could be significant in terms of contributing to AD pathogenesis by affecting the beta amyloid peptide burden. RAP can also modulate the ligand binding activity of LRP through antagonism. As part of our ongoing studies examining mechanisms of beta amyloid clearance from human brain and our previous studies having examined LRP, as well as receptor for advanced glycosalation end (RAGE) products alterations in Alzheimer’s brain, we decided to examine the immunohistochemical expression of RAP in both normal human and Alzheimer’s cortex. There are only a few existing studies examining