Abstract
Although harboring the Apolipoprotein E4 (APOE4) allele is a well-known risk factor in Alzheimer’s disease (AD), whether a similar risk holds true for Parkinson’s disease (PD) is currently not known. To investigate whether apoE pathology is present in PD, an immunohistochemical study was undertaken with fixed, human PD brain sections from the substantia nigra utilizing a recently characterized antibody that detects an amino-terminal fragment of apoE. This antibody, termed the apoE cleavage fragment p17 (nApoECFp17) antibody specifically detects an amino-terminal 17 kDa fragment of apoE without reacting with full-length forms of the protein. Application of this antibody revealed the presence of this fragment in Lewy bodies in all cases examined. Colocalization of nApoECFp17 with an antibody to alpha-synuclein (α-Syn), which served as a general marker for Lewy bodies, indicated the presence of this apoE fragment in 87.5% of all identified Lewy bodies. In addition, localization of nApoECFp17 was also evident within oligodendrocytes, the nucleus of melatonin-containing neurons, and blood vessels. Conversely, little staining was observed in the substantia nigra from Pick’s disease or in the frontal cortex of dementia with Lewy bodies (DLB) cases, suggesting a specificity for nApoECFp17 immunoreactivity in PD. Collectively, these data have identified widespread evidence for apoE fragmentation in the human PD brain and documented for the first time the presence of apoE within Lewy bodies, the major pathological marker for this neurodegenerative disease.
Highlights
Parkinson’s disease (PD) is the second most common age-related, progressive neurodegenerative disorder after Alzheimer’s disease (AD) and is clinically characterized as a movement disorder presenting with rigidity, resting tremor, disturbances in balance and slowness in movement [1]
To determine if amino-terminal fragments of apolipoprotein E (apoE) can be detected in the human PD brain, an immunohistochemical study utilizing the nApoECFp17 antibody was initiated utilizing fixed substantia nigra brain sections from confirmed PD cases
Following application of the nApoECFp17 antibody, widespread labeling was found in all cases examined with prominent labeling observed in apparent Lewy bodies, nuclei of melanin-containing neurons, oligodendrocytes, and along blood vessels (Figure 1)
Summary
Parkinson’s disease (PD) is the second most common age-related, progressive neurodegenerative disorder after Alzheimer’s disease (AD) and is clinically characterized as a movement disorder presenting with rigidity, resting tremor, disturbances in balance and slowness in movement [1]. PD is characterized by the presence of intraneuronal inclusions termed Lewy bodies. Intracytoplasmic inclusions that contain abnormally truncated proteins, including alpha-synuclein (α-Syn) [2,3]. We recently synthesized a site-directed cleavage antibody that recognizes an amino-terminal fragment of 17 kDa (p17) following cleavage after D151 of the mature, full-length form of apoE [13]. This antibody, which we termed the amino-terminal apoE cleavage fragment antibody (nApoECFp17 antibody) is highly specific for this fragment and shows no immunoreactivity to the full-length, 34 kDa form of the protein [13]. We further showed that a recombinantly produced fragment of apoE4, 1-151 was taken up by the microglia cell line, BV2, following extra-
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