**1. Introduction**

Alzheimer's disease (AD) represents the so-called "storage disorder" of amyloid β (Aβ). The AD brain contains soluble and insoluble Aβ, both of which have been hypothesized to underlie the development of cognitive deficits or dementia (1-3). The steady-state level of Aβ is controlled by the generation of Aβ from its precursor, the degradation of Aβ within the brain, and transport of Aβ out of the brain. The imbalance among three metabolic pathways results in excessive accumulation and deposition of Aβ in the brain, which may trigger a complex downstream cascade (e.g., primary amyloid plaque formation or secondary tauopathy and neurodegeneration) leading to memory loss or dementia in AD. Accumulated lines of evidence indicate that such a memory loss represents a synaptic failure caused directly by soluble Aβ oligomers (AβOs) (4-6), whereas amyloid fibrils may cause neuronal injury indirectly via microglial activation (7)**.** Many attentions are paid to understand the mechanism underlying the neurotoxic action of AβOs so far. However, the exact metabolic conditions controlling the *in vivo* generation of soluble AβOs has been out of attention.

Several lines of evidence indicated that lipidic environments in the central nervous system (CNS) represent one of the prevailing metabolic conditions. We then hypothesized that an alteration of the lipoprotein-soluble Aβ interaction in the CNS is capable of initiating and/or accelerating the cascade favoring Aβ assembly (8). We found that dissociation of Aβ42 from lipoprotein in the cerebrospinal fluid from AD accelerates Aβ42 assembly (9). Thus, lipoprotein is a key molecule to maintain monomeric soluble Aβ42 in CNS.

In this chapter, we review the issue regarding how lipoprotein and apolipoproteins contribute to physiological metabolic conditions. Then, we focus on how they constitute the

© 2012 Matsubara, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

AD-related metabolic conditions in the CNS. We are certain that these points of view introduce a novel approach to find a therapeutic intervention for AD.

#### **2. Lipoproteins, apolipoproteins, and Aβ metabolism in the CNS**

In the CNS, we need to be aware that cholesterol metabolism is quite different from that in systemic circulation. Lipidic environments in the CNS were regulated by HDL-like lipoproteins, mainly lipidated apolipoprotein E (apoE), which is in charge of cholesterol transport to and from neurons (10, 11). This is also the case in lipidated apolipoprotein J (apoJ) (12). In addition to lipid trafficking, apoE or apoJ as a form of HDL-like lipoprotein plays a major role in Aβ metabolism in the CNS. Both apolipoproteins are well known as major carrier proteins for Aβ (13-17). Interestingly, transgenic mouse models of AD (apoE- /-/apoJ-/-) revealed that both apolipoproteins regulate in a cooperative manner the clearance and the deposition of Aβ in brain (18). The hypothetical pathways involved in the clearance of CNS Aß are efflux of Aß into the plasma via blood-brain barrier (BBB). Two lipoprotein-receptors, LRP-1 and LRP-2, seem to be responsible for efflux of lipoprotein-free or lipoprotein-associated (apoJ-associated) Aß from the brain to blood, respectively (19). *In vivo* relevance of LRP-1-mediated Aß transport has been confirmed in transgenic mice expressing low LRP-1-receptor and APP, which develops extensive Aß accumulation much faster than transgenic mice expressing high level of APP (20). Reduced expression of brain endotherial LRP-1 was also observed in AD patients, which was associated with impaired Aß clearance and cerebrovascular accumulation. LPR-2 appeared to function bi-directionally (influx vs efflux) at BBB. In contrast to LRP2 mediated influx (21), LPR2-mediated efflux of brain Aß was actively operated under physiological concentration of either Aß or apoJ (19). Interestingly, a recent study shows that apoE4 binding to Aß redirects its clearance from LRP-1 to VLDLR, which resulted in slower efflux of brain Aß than LRP-1 (22). In contrast, apoE2-Aß and apoE3-Aß complexes are cleared at BBB via both LPR-1 and VLDLR at a substantially faster rate than apoE4-Aß complexes(22). Impairment of the above-mentioned receptor-mediated clearance at BBB could contribute to the pathogenesis of AD. Alternatively, ApoE4-HDL shows less cholesterol exchange between lipid particles and the neuronal membrane as compared with apoE3-HDL (23), leading to altered membrane functions, e.g., signal transduction, enzyme activities, ion channel properties, and conformation of sAß peptides, which contribute to the disease-related metabolic conditions. Furthermore, when the generation of HDL-like lipoproteins in the AD mouse model is suppressed or overexpressed via the specific regulation of ATP-binding cassette A1 (ABCA1), Aβ deposition exhibits augmentation or reduction, respectively, which depends on the degree of ABCA1 mediated lipidation of apoE in the CNS (24, 25). From these points of view, lipidic environments in the CNS represent one of the prevailing metabolic conditions. We hypothesized that an alteration of the lipoprotein-sAβ interaction in the CNS is capable of initiating and/or accelerating the cascade favoring Aß assembly. Thus, we postulate that lipoproteins or apolipoproteins may regulate the metabolic conditions controlling the *in vivo* generation of soluble AβOs.

614 Lipoproteins – Role in Health and Diseases

AD-related metabolic conditions in the CNS. We are certain that these points of view

In the CNS, we need to be aware that cholesterol metabolism is quite different from that in systemic circulation. Lipidic environments in the CNS were regulated by HDL-like lipoproteins, mainly lipidated apolipoprotein E (apoE), which is in charge of cholesterol transport to and from neurons (10, 11). This is also the case in lipidated apolipoprotein J (apoJ) (12). In addition to lipid trafficking, apoE or apoJ as a form of HDL-like lipoprotein plays a major role in Aβ metabolism in the CNS. Both apolipoproteins are well known as major carrier proteins for Aβ (13-17). Interestingly, transgenic mouse models of AD (apoE- /-/apoJ-/-) revealed that both apolipoproteins regulate in a cooperative manner the clearance and the deposition of Aβ in brain (18). The hypothetical pathways involved in the clearance of CNS Aß are efflux of Aß into the plasma via blood-brain barrier (BBB). Two lipoprotein-receptors, LRP-1 and LRP-2, seem to be responsible for efflux of lipoprotein-free or lipoprotein-associated (apoJ-associated) Aß from the brain to blood, respectively (19). *In vivo* relevance of LRP-1-mediated Aß transport has been confirmed in transgenic mice expressing low LRP-1-receptor and APP, which develops extensive Aß accumulation much faster than transgenic mice expressing high level of APP (20). Reduced expression of brain endotherial LRP-1 was also observed in AD patients, which was associated with impaired Aß clearance and cerebrovascular accumulation. LPR-2 appeared to function bi-directionally (influx vs efflux) at BBB. In contrast to LRP2 mediated influx (21), LPR2-mediated efflux of brain Aß was actively operated under physiological concentration of either Aß or apoJ (19). Interestingly, a recent study shows that apoE4 binding to Aß redirects its clearance from LRP-1 to VLDLR, which resulted in slower efflux of brain Aß than LRP-1 (22). In contrast, apoE2-Aß and apoE3-Aß complexes are cleared at BBB via both LPR-1 and VLDLR at a substantially faster rate than apoE4-Aß complexes(22). Impairment of the above-mentioned receptor-mediated clearance at BBB could contribute to the pathogenesis of AD. Alternatively, ApoE4-HDL shows less cholesterol exchange between lipid particles and the neuronal membrane as compared with apoE3-HDL (23), leading to altered membrane functions, e.g., signal transduction, enzyme activities, ion channel properties, and conformation of sAß peptides, which contribute to the disease-related metabolic conditions. Furthermore, when the generation of HDL-like lipoproteins in the AD mouse model is suppressed or overexpressed via the specific regulation of ATP-binding cassette A1 (ABCA1), Aβ deposition exhibits augmentation or reduction, respectively, which depends on the degree of ABCA1 mediated lipidation of apoE in the CNS (24, 25). From these points of view, lipidic environments in the CNS represent one of the prevailing metabolic conditions. We hypothesized that an alteration of the lipoprotein-sAβ interaction in the CNS is capable of initiating and/or accelerating the cascade favoring Aß assembly. Thus, we postulate that

**2. Lipoproteins, apolipoproteins, and Aβ metabolism in the CNS** 

introduce a novel approach to find a therapeutic intervention for AD.
