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§
From the Departments of Medicine (Neurology),*
Pathology
(Neuropathology),
and Neurobiology and Joseph
and Kathleen Bryan Alzheimer's Disease Research
Center,
Duke University Medical Center, and
Durham Veterans Administration Medical Center,§
Durham, North Carolina
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The three major alleles of human apoE (APOE2, APOE3, and APOE4) are associated with differences in the age of onset of Alzheimer's disease (AD).20-23 The APOE4 allele is associated with increased risk and earlier age of onset of late-onset AD, whereas the APOE2 allele decreases risk and delays AD onset in genetic studies compared with APOE3/3 individuals.24-26 In addition to its well documented role in AD, the APOE4 allele has been implicated in poorer neurological recovery to head injury, cerebral hemorrhage, and cognitive status after cardiac bypass surgery.27-33 These experiments provide epidemiological evidence for the close relationship of APOE alleles to age of onset and/or outcome in a common human neurodegenerative diseases and in nervous system injury but again do not provide evidence for how apoE may influence the recovery and survival of neurons.
The demonstration that the astrocytic protein apoE can also be found in human neurons is important in assessing this newer role for apoE. In fact, apoE immunoreactivity is found not only in extracellular amyloid deposits but also associated with intracellular neurofibrillary tangles.34-41 In addition, apoE protein-protein interactions observed in vitro also include specific interactions with intracellular neuronal proteins: microtubule-associated proteins (tau, MAP2C).42,43 Moreover, elegant cell culture experiments have demonstrated receptor-mediated uptake of apoE in neurons and large effects on neuritic outgrowth and morphology.8,9,41-48 These results supported an intracellular role for apoE in neuronal pathology in AD and suggested that apoE might be more directly involved in synaptic loss and disruption of neuronal cytoskeleton in addition to postulated effects on ß-amyloidosis.8,42-44 One important consideration in evaluating extracellular versus intracellular hypotheses of the action of apoE is the source of intraneuronal apoE: uptake versus synthesis. A second consideration is the distribution of neurons containing intraneuronal apoE, particularly in brains with little or no neurofibrillary tangle formation.
The apparent normal human and primate pattern of apoE immunolocalization includes many neurons in addition to glial cells. Several studies from our laboratory have shown the presence of immunoreactive apoE in both neurons and glial cells in normal human and primate CNS but essentially restricted to glial cells in normal rodent brain.36,49-51 In humanized transgenic lines carrying genomic sequences for each of the three APOE alleles, in situ hybridization and immunocytochemical localization have demonstrated that apoE has been transcribed and translated not only in glial cells but also in selected populations of cerebral cortical neurons, including hippocampal neurons.51,52 These results in humans, primates, and transgenic rodents suggest that the most important source of intraneuronal apoE may be direct synthesis and not uptake from the extracellular space and that intraneuronal synthesis of apoE may be related to regulatory sequences in the human APOE gene.
To examine the important issue of whether human brain neurons can synthesize apoE, we performed in situ hybridization for APOE mRNA and immunolocalization for apoE in brain tissues collected from five AD patients and three nondemented controls, using the same methods and reagents developed in the human APOE transgenic mice.52
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human brains were collected 3 to 6 hours postmortem from
five AD patients and three clinically examined nondemented patients
with non-neurological disease. One index case was selected for short
postmortem delay and presumed absence of AD pathology, and the other
seven cases were selected randomly from patients enrolled in the Bryan
Alzheimer's Disease Center rapid autopsy protocol.53
Clinical information on all patients was collected from clinic and
hospital records. The pathological diagnosis of AD was established
according to CERAD criteria,54
and the degree of AD
pathological changes was staged according to Braak55
(Table 1)
.
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For all cases, routinely prepared blocks of frontal lobe, temporal lobe, including hippocampal region, and cerebellar cortex taken at autopsy were fixed for 5 to 7 days in 10% formalin and then embedded in paraffin for pathological analysis. The paraffin blocks were cut at 8-mm thickness, and semi-adjacent were sections mounted on coated slides for immunocytochemistry and in situ hybridization.
In addition, specially fixed and cryoprotected blocks of liver and brain were prepared from the index case of a patient with clinical and pathologically confirmed amyotrophic lateral sclerosis (case 1) and used for frozen sections according to published protocol.51 These blocks of frontal lobe, hippocampal region, cerebellum, and liver were left in 10% formaldehyde in 0.1 mol/L phosphate buffer (pH 7.4) overnight at 4°C and transferred to a solution of 20% sucrose in phosphate buffer overnight at 4°C. The tissues were then placed in tissue-freezing medium (Triangle Biomedical Sciences, Durham, NC), frozen in liquid-nitrogen-cooled ethane, and stored at -70°C before sectioning. Cryostat sections were cut at 8 mm and collected on gelatin-coated slides for in situ hybridization and immunolocalization.
Immunocytochemistry
Immunocytochemistry was performed using avidin-biotin-peroxidase complex (ABC) methods using Elite Vector ABC kits (Vector Laboratories, Burlingame, CA). Sections were deparaffinized, treated with 90% formic acid for 3 to 5 minutes, washed, and then permeabilized with 0.1% Triton X-100 for 10 minutes. After washing with PBS three times, 10 to 15 minutes of methanol-peroxide pretreatment (10% methanol/3% hydrogen peroxide) was used to decrease endogenous peroxidase activity. The treated sections were blocked with avidin/biotin blocking reagent (Vector) and incubated with polyclonal goat antiserum to human apoE (Calbiochem, La Jolla, CA) diluted at 1:500 with Tris-buffered saline (TBS), pH 7.5, containing 0.1% Tween-20 for 30 minutes at 37°C. After thoroughly washing with TBS, the sections were exposed sequentially to biotinylated secondary antibodies and avidin-biotin-peroxidase complex for 30 minutes each at 37°C separated by washes. Vector VIP substrate kit was used to detect bound ABC complex.
Preparation of cRNA Probes
Human APOE cDNA fragments specific for APOE3 allele (courtesy of Dr. D. Goldgaber, Stony Brook, NY) were cloned into Bluescript SK vector (Stratagene, La Jolla, CA) at the EcoRI restriction site. Digoxigenin-labeled cRNA (DIG-cRNA) probes in the antisense and sense orientation were synthesized from linearized templates by using bacterial T3 and T7 polymerases, respectively, in the presence of DIG-11-UTP, as described by the manufacturer (Boehringer Mannheim, Indianapolis, IN).
Southern Blot Analysis, Southern Slot Blotting, and Northern Blot Analysis
Southern blot analysis was performed51 to test for specific hybridization of antisense and sense DIG-cRNA probes to APOE cDNA fragments. The sensitivity of the DIG-cRNA probes was analyzed by slot blotting for detection of APOE cDNA plasmids. Northern blotting51 was used to examine whether the antisense DIG-cRNA probe had specific hybridization to APOE mRNA but not to the similarly prepared sense probe. Total RNA was extracted from human brain frontal lobe as described previously51 and from similarly prepared mouse brain from APOE allele-specific transgenic51 lines APOE2–205, APOE3–437, and APOE4–81 and from APOE knockout mice56 as positive and negative controls. Fifteen micrograms of each RNA sample was separated by 1.0% agarose gel and transferred to GeneScreen filters. The identical parallel filters were hybridized with the same antisense and sense DIG-cRNA APOE probes used for in situ hybridization. The hybridization signal on the GeneScreen filter was visualized using anti-DIG antibody conjugated with the alkaline phosphatase detection kit using the manufacturer's protocol (Boehringer Mannheim).
In Situ Hybridization
In situ hybridization for human APOE mRNA was performed using the same methods developed in human APOE transgenic mice.52 In initial experiments, hybridization was tried at 55°C, 65°C, and 70°C. Hybridization at high temperature (70°C) yielded the best signal and lowest background compared with higher background at lower hybridization temperatures as human APOE mRNA has a high GC content.52,57,58 Prehybridization was carried out for 1 to 3 hours at room temperature (RT) in prehybridization buffer consisting of 50% formamide, 5X SSC, 10% dextran sulfate, 100 mmol/L dithiothreitol, 250 µg/ml Baker yeast tRNA, and 10 U/ml RNAse inhibitor (Gibco-BRL, Gaithersburg, MD). The hybridization mixtures were prepared by adding 50 to 100 ng/ml DIG-cRNA probes to the prehybridization buffer and then heated 5 minutes at 95°C to denature the probes. Hybridization was allowed to proceed for 16 hours at 70°C in a humid chamber. After washing three times with 2X SSC at 60°C and once with 0.2X SSC at room temperature for 15 minutes each wash, the sections were incubated for 30 minutes at room temperature with alkaline-phosphatase-conjugated anti-DIG antibody diluted at 1:1000. After three to five washes, the sections were developed using an alkaline phosphatase detection kit following the manufacturer's protocols (Boehringer Mannheim).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To confirm the specific hybridization of APOE cRNA
probes with human APOE cDNA and mRNA, Southern blot,
Southern slot blot, and Northern blot analyses were performed using
antisense and sense digoxigenin-labeled APOE cRNA (DIG-cRNA)
probes. Southern blot results showed that both antisense and sense
DIG-cRNA probes hybridized specifically with expected the 1163-bp
APOE cDNA fragments (Figure 1A)
. Both the sense and antisense
DIG-cRNA probes were able to detect between 1.0 and 10 ng of
APOE plasmid cDNA in Southern slot blot analysis (Figure 1B)
. Northern blot analysis demonstrated that only the antisense
APOE DIG-cRNA probe showed specific hybridization with human
APOE mRNA in total RNA extracted from human brains and
APOE transgenic mouse brains under the same conditions
(Figure 1C)
. Sense DIG-cRNA probes did not hybridize with
APOE mRNA in the parallel Northern blot (Figure 1C)
. No
hybridization signal was detected in RNA extracted from APOE
knockout mouse brain using antisense DIG-cRNA probe. These results
support specific hybridization of antisense APOE DIG-cRNA
probes to blotted APOE mRNA.
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. Chromogen development times were
controlled to produce minimal signal in sections of human liver (Figure 2A)
and brain (Figures 3A, 4, A and D, and 6A)
processed in parallel
using sense APOE DIG-cRNA probe. These reagents and methods
have been described in APOE transgenic mice where antisense
APOE DIG-cRNA probe permits specific detection of human
APOE mRNA.52
The present and published in
situ hybridization results support the conclusion that the
antisense APOE DIG-cRNA probe specific hybridizes
with intracellular human APOE mRNA in brain and liver
tissues.
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In human cerebellar cortex, very strong APOE mRNA
hybridization signal was observed in Bergmann radial glial cells and in
some scattered astrocytes (Figure 3)
. Similar localization was observed
in both frozen (Figure 3C)
and paraffin-embedded sections (Figure 3, B and D)
in nondemented control and AD patients. Localization of in
situ hybridization signal was entirely consistent with the pattern
of immunoreactive apoE localization in sections from the same brains
(Figure 3E)
. No apparent evidence for neuronal APOE mRNA
hybridization or neuronal apoE immunolocalization was observed in
cerebellar cortex of these human brains (Figure 3, B–E)
. The
expression of the human APOE gene in Bergmann glial cells
was very strong, and hybridization signal often extended for
considerable distances into their radial processes extending outward in
the molecular layer. In normal and transgenic rodent cerebellar cortex,
apoE immunoreactivity in Bergmann glia and their long radial fiber
processes is typically intense.6,51
This normal
glial-specific apoE immunolocalization and APOE mRNA
hybridization pattern in human cerebellar cortex corresponds to that
observed in humanized mice transgenic for genomic fragments of human
APOE gene and in normal wild-type mice.52
Neuronal and Glial APOE mRNA Transcription and Expression in Frontal Cortex
In frontal cortex and hippocampus (Figure 4)
, the pattern of
in situ hybridization for human APOE mRNA was
remarkably different from that observed in cerebellar cortex of the
same cases (Figure 3)
. APOE mRNA hybridization signal could
be observed in selected populations of large neurons in frontal lobe
(Figure 4, B and C)
and in frozen sections of hippocampus (Figure 4E)
.
The APOE mRNA hybridization signal intensity for neurons
varied markedly. The number and distribution of neurons with
APOE mRNA hybridization signal was similar to the pattern of
immunocytochemical localization of neuronal apoE in parallel sections
(case 5, Figure 4, C and F
). Often, the relative APOE mRNA
hybridization signal was stronger in presumptive astrocytes or glial
cells compared with neurons (Figure 4E)
. The number and distribution of
APOE mRNA-positive neurons and relative glial/neuronal
intensity differences were qualitatively similar to the pattern
observed in transgenic mice carrying human APOE genomic
fragments.51,52
We observed APOE mRNA-positive
and apoE-immunoreactive neurons in cerebral regions with AD pathology
(case 5), including apoE-immunoreactive senile plaques (Figure 4, C and F)
. This result was consistent with our previous reports on apoE
immunoreactivity of neurons and senile plaques.36
Neuronal and Glial APOE mRNA Transcription and Expression in Hippocampus
In sections of human hippocampus, APOE mRNA
hybridization signals were observed in neurons in all of the cases,
including nondemented controls and AD patients (Figures 5 and 6
and
in presumptive glial cells. The typical appearance of
apoE-immunoreactive granule cell neurons is illustrated in Figure 5A
for the granular cell layer of the dentate gyrus, similar to our
previous report.36
APOE mRNA hybridization
signal was present in a similar number of neurons in the granule cell
layer of the dentate gyrus (Figure 5B)
. APOE mRNA-positive
neurons were observed in the granule cell layer of the dentate gyrus
adjacent to more numerous nonhybridizing neurons (Figure 5B)
.
APOE mRNA-positive neurons were observed in all sectors of
the hippocampus, illustrated for CA1–2 (Figure 6B)
, CA3 (Figure 6, D and E)
, and CA4 (Figure 6, G and H)
and adjoining temporal cortex
(Figure 4E)
. No appreciable hybridization signal was visualized in the
sections probed in parallel with the sense DIG-cRNA probe as
illustrated for the CA1–2 sector (Figure 6A)
. These observations
support the proposition that the antisense probe hybridization signal
was specific for cells containing APOE mRNA sequence.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. This is a new finding, and we have been
careful to exclude as best as possible other reasons for these
observations. We have verified that both antisense and sense
APOE DIG-cRNA probes used in these experiments can
specifically hybridize with APOE cDNA on Southern blot
(Figure 1A)
and that only the antisense probe hybridizes with human
APOE mRNA on Northern blot (Figure 1C)
. In addition, no
hybridization signal is visualized on human brain and liver sections
processed in parallel and probed with the sense probe (Figures 3A, 4A, and 6A)
. The antisense probe detects human APOE mRNA in
transgenic mice,52
but no hybridization signal is observed
for sense or antisense probe in APOE knockout
mice.52
The observation of regional specificity in terms of
neuronal hybridization (see below) further supports the conclusion that
neuronal hybridization is specific for the presence of APOE
mRNA. Thus, the present reagents and methods apparently provide a
reliable assay for localization of APOE mRNA in human brain.
The pattern of transcription and expression of APOE mRNA in
human brain neurons is apparently regionally specific based on
examination of cerebellar cortex, frontal cortex, and hippocampus. This
pattern is entirely similar to our findings in mice transgenic for
genomic fragments of the human APOE gene.51,52
APOE mRNA is present in some, but not all, neurons in
frontal cortex and hippocampus in the cases in our series (Figures 4E, 5B, and 6
, D and E) apparently unrelated to extent of AD pathology. The
apparent number and distribution of neurons containing APOE
mRNA is qualitatively similar to the number and distribution of
apoE-immunoreactive neurons (Figures 4F, 5A, and 6, C and F
). In
striking contrast, neither APOE mRNA nor apoE
immunoreactivity is detected in cerebellar cortical neurons (Purkinje
cells, stellate-basket cells, and granule cells) in these same cases
(Figure 3)
. The pattern of intense apoE immunoreactivity of Bergmann
glial cells and their long radial processes and the lack of neuronal
apoE immunoreactivity seen in human cerebellar cortex is similar to the
pattern observed in normal rat and mouse.6,51,52
The
presence of apoE-immunoreactive neurons in human frontal cortex and
hippocampus in the present series confirms our previous published
results.36,42,50
ApoE-immunoreactive neurons are also
observed in a regionally specific pattern in mice transgenic for
genomic fragments of human APOE gene.51,52
We
have not yet examined other human brain regions or examined the issue
of influence of APOE genotype on these results.
The pattern of APOE mRNA localization and apoE
immunoreactivity is qualitatively similar in the present series,
particularly in the striking regional differences between cerebral
cortex and cerebellum. However, we observed relatively fewer
APOE mRNA-positive neurons than apoE-immunoreactive neurons
in cerebral cortex and hippocampus of these AD patients and normal
controls. In the frozen sections, we observed typical relatively weaker
APOE mRNA signals in neurons than adjacent astrocytes
(Figures 4E and 6H)
. This may reflect a sensitivity threshold of our
antisense APOE DIG-cRNA probe, or more likely a lesser
amount of APOE mRNA in neurons. The limitation of detection
for APOE mRNA in neurons may depend on several factors.
Failure to detect APOE mRNA in neurons in other studies to
date18,19,59
could be due to less sensitive or specific
probes used, loss of mRNA during agonal events, tissue preparation or
cutting and mounting of sections, too high a stringency of
hybridization and/or prolongation of washing steps, and the relative
signal-to-noise characteristics of the detection system.
Whether apoE can be synthesized by neurons in normal human brain is
fundamental to understanding the demonstrated role of the human
APOE gene and its alleles as a susceptibility gene in
late-onset AD20-23,43
and the additional role of
APOE alleles in some forms of CNS injury. Cognitive decline
in AD is most directly associated with neuronal loss and cytoskeletal
abnormality, including neurofibrillary tangles, in which the principal
constituent is hyperphosphorylated tau, a microtubule-associated
protein.38
One hypothesis for the role of APOE
alleles in the pathogenesis of AD is a proposed influence on
intraneuronal metabolism through interaction with neuronal cytoskeletal
proteins, microtubule-associated proteins tau and
MAP2.42,43
In the brains of patients with AD pathology, it
is generally accepted that apoE is present in many neurons with
neurofibrillary tangles.34,39,60,61
In normal controls, AD
patients and nonhuman primates, apoE-immunoreactive neurons without
apparent cytoskeletal pathology are also observed in hippocampus and
cerebral cortex.49,50
In rodent experiments with brain
injury induced by ischemia and kainic acid, apoE mRNA and apoE
immunoreactivity are seen in neurons in injured areas and might reflect
neuronal synthesis of apoE.14-16
APOE alleles
have been proposed to affect the degree of cholinergic injury in
Alzheimer's disease through mechanisms of altering synaptic
plasticity.62,63
Although we cannot rule out the expected
receptor-mediated neuronal uptake of apoE,45-48
the
findings reported here describing specific neuronal hybridization for
human APOE mRNA do not support the commonly held idea that
apoE is synthesized and secreted only by non-neuronal cell classes in
human CNS.4-7
We observed APOE mRNA-positive
neurons in cerebral regions from normal controls as well as cases with
AD pathology, including apoE-immunoreactive neuritic plaques (Figure 4, C and F)
. This suggests that the previously described presence of
apoE-immunoreactive neurons in human brain, both in normal and AD
cases, may represent neuronal synthesis.34,36,49,60,61
The
cerebellum, with very strong glial and lack of neuronal APOE
transcription in all of the cases, is a relatively spared structure in
AD compared with cerebral cortex. This same in situ
hybridization pattern is also seen in our humanized APOE
allele-specific transgenic mice.51,52
These results in
cerebellum and cerebral cortex indicate that human APOE gene
expression in neurons may be one factor or marker for selective
vulnerability of cerebral cortical neurons observed in
AD.54,64
In this report, we have examined a limited series of recent nondemented control cases and AD patients for in situ hybridization for APOE mRNA. We have seen APOE mRNA transcription in selected neurons in all brains examined to date. These results cannot speak to possible quantitative difference or to effects of representative APOE alleles and many other factors. Our results do not permit any conclusions about whether more subtle or systematic differences in degree of neuronal APOE transcription and expression may exist between normal nondemented controls and AD patients. The regionally specific pattern of human APOE gene expression observed in the brains of transgenic mice51,52 is confirmed for human frontal cortex, hippocampus, and cerebellum, but we have not yet examined other brain regions. In addition, additional experiments with more extensive series comparing nondemented controls and AD patients with the various APOE genotypes will be necessary to comment on possible differences related to APOE allelic variation. These experiments will be necessary to define the limit conditions for neuronal transcription and expression of the APOE gene and the significance for neuronal metabolism, aging, and response to injury. Regionally specific intraneuronal synthesis of apoE may be a significant factor in regional vulnerability of neurons to cytoskeletal pathology and in interactions of apoE with neuronal proteins. For both intraneuronal synthesis and receptor-mediated uptake of apoE, there are significant questions as to the conditions under which this protein might gain access to the cytoplasmic compartment to participate in such interactions.
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Acknowledgements |
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Footnotes |
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Supported by NIH-NIA Alzheimer's Disease Research Center (AG-05128) and numerous private research gifts to the Duke University Alzheimer's Disease Research Center.
Accepted for publication October 26, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993, 43:1467-14724 allele and familial aggregation of Alzheimer disease. Arch Neurol 1998, 55:810-8164 in patients with Alzheimer's disease. Neurology 1995, 45:555-557
2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res 1992, 269:375-382[Medline]
2 macroglobulin receptor in Alzheimer and control postmortem human brain. Mol Chem Neuropathol 1993, 18:153-159[Medline]
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