Lipoprotein Receptors in Alzheimer´s Disease: Beyond Lipoprotein Transport

The LDL-receptor gene family constitutes a class of structurally closely related cell surface receptors fulfilling diverse functions in different organs, tissues, and cell types. The LDL-receptor is the prototype of this family, which also includes the VLDLR, ApoER2/LRP8, LRP1 and LRP1B, as well as Megalin/GP330, SorLA-1/LR11, LRP5, LRP6 and MEGF7. Recently several lines of evidence have positioned the LDL receptor gene family as one of the key players in Alzheimer’s disease (AD) research. Initially this receptor family was of high interest due to its key function in cholesterol/apolipoprotein E (ApoE) uptake, with the ε4 allele of ApoE as the strongest genetic risk factor for late-onset AD. It has been established that the cholesterol metabolism of the cell has a strong impact on the production of Aβ, the major component of the plaques found in the brain of AD-patients. The original report that soluble amyloid precursor protein (APP) containing the kunitz proteinase inhibitor (KPI) domain might act as a ligand for LRP1 led to a complex investigation of the interaction of both proteins and their potential function in AD development. Meanwhile, it has been demonstrated that LRP1 might bind to APP independent of the KPI domain in APP. This APP – LRP1 interaction is facilitated through a trimeric complex of APP-FE65-LRP1, which has a functional role in APP processing. Along with LRP1, APP is transported from the early secretory compartments to the cell surface and subsequently internalised into the endosomal / lysosomal compartments. Recent investigations indicate that VLDLR, ApoER2 and SorLA fulfil a similar role in shifting APP localisation in the cell, which affects APP processing and the production of the APP derived Amyloid β-peptide (Aβ).

In addition to the effect of lipoprotein receptors on APP processing and Aβ production, LRP1 has been shown to bind Aβ directly or indirectly through Aβ-lactoferrin, Aβ-α2M and Aβ-ApoE complexes in vitro and in vivo. Therefore based on these observations two LRP1 mediated clearance mechanisms of Aβ are proposed to play a crucial role in the prevention of AD: either Aβ-uptake into a cell with its subsequent degradation or its transport out of the brain over the blood brain barrier into the periphery. Following this export Aβ is degraded in the liver, where LRP1 potentially conducts the removal of Aβ from the blood stream.

Although the involvement of LDL-R-family members in AD is not yet fully understood it becomes clear that they can directly affect APP production, Aβ-clearance and Aβ-transport over the blood brain barrier as well as NMDA receptor function.

Keywords: LDL receptor family, alzheimer´s disease, blood-brain-barrier, ApoE, ApoE4, amyloid precursor protein, Fe65, VLDL receptor, LRP1, SorLA, RAGE, ApoE2 receptor, cholesterol, shedding, amyloid beta Aβ, Aβ clearance, NPxY motif, BACE, gamma-secretase.