Macrophage colony stimulating factor is associated with excretion of amyloid-β peptides from cerebrospinal fluid to peripheral blood

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The process of aggregation of brain amyloid-β peptides (Aβ) is thought to be associated with the pathogenesis of Alzheimer's disease (AD). Amyloid-β peptides are produced by sequential endoproteolysis by β-site amyloid-β protein precursor-cleaving enzyme (BACE) followed by presenilin (PS)/γ-secretase. There are several species of Aβ due to cleavage diversity of PS/γ-secretase. The predominant species in human cerebrospinal fluid (CSF) or plasma is Aβ40, whereas Aβ42 is much more aggregatable and accumulated in senile plaques. The level of Aβ in the brain is determined by the balance between the generation and clearance of Aβ, including transport across the brain–blood barrier (BBB). Although the processes of Aβ generation and degradation have been studied in some detail, knowledge of the Aβ transport process across the BBB is limited. So far, low-density lipoprotein receptor-related protein (LRP1), P-glycoprotein (P-gp), and insulin-like growth factor-1 (IGF-1) have been identified to modify the excretion of brain Aβ to the blood.


To investigate whether macrophage colony stimulating factor (M-CSF) has a role in the Aβ transport process, human Aβ was injected into the lateral ventricle of the brain of M-CSF-deficient (op/op) mice. Then, plasma and brain Aβ levels were measured by ELISA to determine the time-course of Aβ movement from the brain to the plasma.


When human Aβ40 was injected into mouse lateral ventricles, the efflux of Aβ from the CSF to the blood was transiently decreased and delayed in M-CSF-deficient mice. Moreover, endogenous plasma Aβ40 levels were lower in M-CSF-deficient mice.


The results indicate that M-CSF deficiency impairs excretion of human-type Aβ40 from the CSF to blood. We propose that M-CSF may be a novel factor that facilitates the excretion of Aβ from the CSF to the blood via the BBB.

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