Modulation of apolipoprotein E (ApoE) receptor-2 by ApoE4, amyloid ꞵ-peptide, reelin, and secreted amyloid precursor protein: a common point of impact in Alzheimer's disease pathogenesis

Steven W Barger^1,2*Andrea M Moerman-Herzog¹

• ¹University of Arkansas for Medical Sciences, Little Rock, United States
• ²Central Arkansas Veterans Healthcare System John L McClellan Memorial Veterans Hospital, Little Rock, United States

Apolipoprotein E (ApoE), reelin, and several other proteins bind ApoE-receptor 2 (apoER2), distinguished from other members of its receptor family by signal transduction which enhances the activity of N-methyl D-aspartate (NMDA) receptors. Evidence indicates that this signal transduction depends upon apoER2 forming dimers or other high-order clusters. It seems noteworthy therefore that protein products of major APOE gene variants differ in their numbers of cysteines capable of forming disulfide dimers, with the allele (ε4) associated with highest rates of Alzheimer's disease (AD) possessing none. Thus, lower AD risk may be associated with the ability of ApoE to dimerize and thereby promote apoER2 dimerization and signaling. We found that reelin and ApoE3—the product of the APOE ε3 allele—elevated calcium fluxes via the NMDA receptor, and this phenomenon required apoER2. By contrast, the product of the ε4 allele antagonized activation. Various aggregation forms of amyloid β-peptide (Aβ) also differed in their ability to activate apoER2: fibrillar Aꞵ appeared to activate apoER2, and oligomeric Aβ antagonized activation by reelin. Prior studies documented a binding between reelin and the Aβ precursor protein (APP), and our results indicated that secreted APP (sAPP) interacted with reelin to augment its effects on apoER2; and while sAPP alone was not an agonist, high-affinity binding of sAPP to apoER2 was detected. These findings suggest a comprehensive hypothesis for the pathogenesis of AD whereby the common factor in development of disease is antagonism of apoER2, likely to include competitive interference with multimeric ligands by agents that cannot promote the receptor's dimerization.