**4. Aß is present in either lipoprotein-free or lipoprotein-associated form in cerebrospinal fluid (CSF)9**

The presence of lipoprotein-free sAβOs in CSF was also assessed in age-matched normal controls (NCs) and patients with Alzheimer's disease (AD) by SEC and ELISA specific for either AβOs or AβMs. The SEC experiment using pooled CSF revealed that the dissociation of sAβMs from lipoprotein particles indeed occurs in CSF, which was lower in AD than in NCs. Furthermore, the SEC experiment using lipoprotein-depleted pooled CSF (LPD-CSF) confirmed the presence of oligomeric 2C3 conformers (4- to 35-mers), which appeared to be higher in AD patients than in NCs. To address the issue on the presence of any metabolic conditions favoring Aβ assembly, we compared the levels of lipoprotein-free sAβMs and sAβOs in LPD-CSF from the 12 sporadic AD patients and 13 NCs to evaluate the AβOs/ AβMs ratio (the O/M index). The levels of 2C3 oligomeric conformers composed of Aβ42 are significantly higher in AD patients than in NCs. The O/M index for either Aβ42 or Aβ40 is also significantly higher in AD patients than in NCs. Of note, the relative amounts of total lipoprotein-associated sAβMs (~70%) versus lipoprotein-free sAβMs (~30%) remained

**Figure 1.** Hypothetical metabolic conditions favoring Aβ assembly. Functionally declined lipoproteins may accelerate the generation of metabolic conditions leading to higher levels of soluble Aβassembly in the CNS.

essentially unchanged in sporadic AD patients as compared with NCs. However, the relative amounts of lipoprotein-free Aβ42 was significantly lower in the sporadic AD patients (9.3 ± 3.9 %) than in NCs (13.2 ± 4.5 %), which is in accordance with our abovementioned finding that the level of oligomeric 2C3 conformers composed of Aβ42 was significantly elevated in AD patients. Thus, it is likely that the conversion of lipoprotein-free monomeric soluble Aβ42 into oligomeric assembly preferentially occurs in AD CSF, mirroring the disease-related metabolic conditions in the brain parenchyma.

#### **5. Summary**

616 Lipoproteins – Role in Health and Diseases

the CNS.

**Figure 1.** Hypothetical metabolic conditions favoring Aβ assembly. Functionally declined lipoproteins may accelerate the generation of metabolic conditions leading to higher levels of soluble Aβassembly in

**HDLlipoproteins**

**apo E**

**Aβ clearance Aβ assembly**

**Aβ**

**apo J**

We previously reported that ~90% of sAβMs that circulate in normal plasma is associated with lipoprotein particles (27). From the above data, it is plausible to assume that about 70% of CSF sAβMs is normally associated with lipoprotein particles, indicating that CNS constitutes a risky environment where the lipoproteins-sAβMs interaction is impaired, leading to Aβ assembly. From this point of view, a key molecule to maintain monomeric sAβ42 metabolism in CNS appears to be HDL-like lipoprotein particles. In this sense, the dissociation of sAβ42 from or the lack of association with HDL-like lipoprotein particles not only constitutes a potential mechanism to initiate and/or accelerate the cascade favoring Aβ42 assembly in the brain, but also results in a reduced clearance of physiological lipoprotein-associated sAβ42 peptides in the brain. Thus, above-mentioned CNS environments may strongly affect conformation of sAβ peptides, resulting in the conversion of sAβ42 monomers into sAβ42 assembly. The findings suggest that functionally declined lipoproteins may accelerate the generation of metabolic conditions leading to higher levels of sAβ42 assembly in the CNS.

#### **Author details**

Etsuro Matsubara *Department of Neurology, Institute of Brain Science, Hirosaki Graduate School of Medicine, Japan* 

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Extracellular and Intraneuronal HMW-AbetaOs Represent a Molecular Basis of Memory Loss in Alzheimer's Disease Model Mouse. Mol Neurodegener. 2011;20: 6.

**Lipoproteins and Cancer** 

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Extracellular and Intraneuronal HMW-AbetaOs Represent a Molecular Basis of Memory Loss in Alzheimer's Disease Model Mouse. Mol Neurodegener. 2011;20: 6.
