Abstract
Polymorphic variation in the apolipoprotein E (apoE) gene is the major genetic susceptibility factor for late-onset Alzheimer's disease (AD) and likely contributes to neuropathology through various pathways. It is also recognized that apoE undergoes proteolytic cleavage in the brain and the resultant apoE fragments likely have a variety of bioactive properties that regulate neuronal signaling and may promote neurodegeneration. ApoE fragmentation in the human brain has been intensively studied using different immunochemical methods, but has never been analyzed in a quantitative manner to establish preferably accumulated fragments. Here we report quantification using multiple reaction monitoring mass spectrometry (MRM MS) with 15N-labeled full-length apoE4 as an internal standard. Measurements were performed on frontal cortex from control and severe AD donors. Our data point to a preferable accumulation of C-terminal apoE fragment in the insoluble fraction of tissue homogenate in the severe AD group versus the control group. Further insight into the biological consequences of this accumulation may lead to a better understanding of the basic mechanism of AD pathology.
Highlights
Apolipoprotein E is a glycoprotein that was initially recognized for its importance in lipid transport in peripheral circulation and the central nervous system
Human Apolipoprotein E (apoE) has three major isoforms, apoE2, apoE3, and apoE4, which differ by single amino acid substitutions involving cysteine-arginine replacements at positions 112 and 158 [1].ApoE4 (e4 allele) is a major genetic risk factor for late-onset Alzheimer’s disease (AD) [2]
Several lines of evidence point to the fact that apoE4 is highly susceptible to proteolysis compared to apoE3, and that the link between apoE4 and AD may be in generation of stable fragments that enhance pathology.ApoE (
Summary
Apolipoprotein E (apoE) is a glycoprotein that was initially recognized for its importance in lipid transport in peripheral circulation and the central nervous system. It has been studied for its role in Alzheimer’s disease (AD). Fragments generated by off-hinge cleavage were reported These include a 30 kDa N-terminal fragment (carboxyl-terminal-truncated apoE), which is generated by cleavage at sites within the C-terminal domain [4,9], and an 18 kDa N-terminal fragment, which is generated by cleavage within the N-terminal domain [4,9,10]. The relative distribution between soluble and insoluble cell fractions remains unclear
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