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From the Department of Cell and Molecular Biology *
Institute, for Neuroscience, Northwestern University Medical School,
Chicago, Illinois; the Program in Cognitive Neuroscience and
Schizophrenia,
Nathan Kline Institute for
Psychiatric Research, Orangeburg, New York; the ICOS
Corporation,
Bothell, Washington; the
Department of Neurological Sciences,§
Rush
Alzheimer's Disease Center, Rush-Presbyterian-St. Luke's Medical
Center, Chicago, Illinois; and the Department of Medical
Biochemistry,¶
Ohio State University College of
Medicine, Columbus, Ohio
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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,
Cki
, and Cki
) in AD and control brains using
immunohistochemistry and Western analysis. In addition to colocalizing
with elements of the fibrillar pathology, CK1 is found within
the matrix of granulovacuolar degeneration bodies. Furthermore,
levels of all CK1 isoforms are elevated in the CA1 region of AD
hippocampus relative to controls, with one isoform,
Cki, being elevated >30-fold. We propose that
overexpression of this protein kinase family plays a key role in the
hyperphosphorylation of tau and in the formation of AD-related
pathology.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5 µm diameter) vacuoles
containing a dense-cored granule.1
The
molecular composition of GVD bodies,
which appear primarily within the cell bodies of affected hippocampal
pyramidal neurons, is unknown. The second lesion, characterized by the
accumulation of fibrils or filaments within neuronal cell bodies
(neurofibrillary tangles; NFT), neuronal processes (neuropil threads),
and within dystrophic neurites associated with amyloid plaques
(neuritic plaques; NP), comprises the neurofibrillary or fibrillar
pathology. Each manifestation of fibrillar pathology accumulates
filaments comprised of the microtubule-associated protein
tau.2
As a result, affected brain regions contain nearly
an order of magnitude more tau than normal controls.3
In
addition to these quantitative differences, the quality of tau differs
as well, having fold higher stoichiometries of covalently bound
phosphate than normal tau.4
Hyperphosphorylation affects
tau function5
and is a sensitive marker of
disease.6
Multiple strategies have been used to identify the phosphotransferases
mediating tau hyperphosphorylation in AD. First, in vitro
approaches have proved that tau is an efficient substrate for most
protein kinases, many of which are capable of filling known
phosphorylation sites on filamentous tau.7
These studies
have shown that the number of phosphotransferases involved in tau
hyperphosphorylation is potentially large. Cell-based approaches
confirm that elevation of selected protein kinases in situ
can increase occupancy of sites found on filamentous tau,8
but again it is not clear which of these enzymes may actually be
involved in disease pathogenesis. A third approach has focused on
authentic AD tissue to identify phosphotransferases that are tightly
associated with elements of AD pathology or that change levels
or specific activity in disease. Applying the last strategy, we
showed that the principal phosphotransferases associated with AD
brain-derived tau filaments are members of the casein kinase-1 (CK1)
family of protein kinases.9
Once considered a single
entity, human CK1 is now known to consist of multiple isoforms encoded
by distinct genes (Cki, 
1, 2, 3, , ). At least one of
these isoforms, Cki, was shown to be a major constituent of purified
tau filaments, comprising as much as 0.5% of the preparation by
weight, suggesting it is localized appropriately to play a role in tau
hyperphosphorylation.9
Here we tested the hypothesis that CK1 isoforms correlate with AD
pathogenesis by returning to authentic AD tissue and examining the
distribution of isoforms Cki, , and by immunohistochemistry
and Western analysis. The results confirm that CK1 isoforms associate
with elements of AD pathology in tissue, with large increases in levels
accompanying the formation of AD pathology in hippocampus. Furthermore,
the data presented here establish CK1 isoforms as unambiguous markers
for GVD in AD tissue, suggesting a regulatory nexus between GVD and the
fibrillar pathologies.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monoclonal antibodies specific for Cki (IC94.1),9
Cki (IC128A),9
class IIIß isoform of tubulin
(Tuj1),10
and filamentous tau (Tau2)11
were
purified and handled as described.12
Purified monoclonal
antibody against Cki came from a commercial source (#40520;
Transduction Laboratories, Lexington, KY).
Human Subjects
AD cases had a clinical diagnosis of probable AD that was confirmed on neuropathological evaluation in which the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) age-adjusted criteria were met. Control cases were nondemented clinically and failed to fulfill the age-adjusted neuropathological criteria for AD.13
Tissue Preparation
Postmortem interval for all specimens averaged 8.8 ± 5.6 hours (range, 4–20 hours). For all immunohistochemical analyses described below, brains from four AD patients (one female and three males, mean age 81.8 ± 2.6 years; range, 78–84 years) and three nondemented controls (one female and two males, mean age 66.0 ± 2.0 years; range, 64–68 years) were harvested, sliced into 1-cm-thick coronal slabs, and fixed in chilled 4% paraformaldehyde for 30 hours as described.14 Fixed slabs containing the hippocampus and adjacent temporal cortices were cut into 40-µm-thick sections on a freezing sliding microtome and stored in cryoprotectant until processed.
For preparation of homogenates, hippocampi were dissected from five AD patients (three female and two males, mean age 67.0 ± 4.9 years; range, 63–75 years) and four age-matched controls (two female and two males, mean age 65.3 ± 2.9 years; range, 63–69 years), snap-frozen in liquid nitrogen, and stored at -80°C until processed. All samples were coded and analyzed by an investigator blinded to the code.
Immunohistochemistry
Free-floating, 40-µm-thick tissue sections were processed for immunohistochemistry as described,14 except that 1% nonfat dry milk replaced horse serum in all incubations involving antibodies. Sections were immunostained with monoclonal antibodies IC94.1 (10 µg/ml), IC128A (2 µg/ml), 40520 (1 µg/ml), or Tau2 (2 µg/ml) overnight at room temperature. Biotinylated goat anti-mouse antibody (6.8 µg/ml;Vector Laboratories, Burlingame, CA) was used as secondary antibody. Stained sections were labeled for 1 h in an avidin-biotin complex (Elite kit; Vector Laboratories; diluted 1:275), developed with 3,3'-diaminobenzidine (Metal enhanced DAB Substrate Kit, Pierce, Rockford, IL), mounted on gelatin-coated slides, dehydrated through graded alcohols (70, 90, 100%), cleared in xylene, and coverslipped with Permount (Fisher Scientific, Pittsburgh, PA). Selected sections were counterstained with cresyl violet (0.11% in H2O) or Thioflavin S (0.1% in H2O) before dehydration. Paraffin-embedded sections (6 µm) were treated similarly after dewaxing, except that they were heat treated (120°C for 7 minutes in 10 mmol/L Tris-NaOH, pH 10.0 at 25°C) before immunostaining.15 To clarify whether monoclonal antibodies recognized phosphoepitopes, selected sections were dephosphorylated with calf intestine alkaline phosphatase (Type VII-L, Sigma, St. Louis, MO) before immunohistochemistry as described previously.11,16
Immuno-Electron Microscopy
Coronal sections of hippocampus (40 µm) were subjected to immunohistochemistry as described above, except that Triton X-100 was omitted from all solutions. Immunostaining was detected with either 3,3'-diaminobenzidine or silver-enhanced colloidal gold.17 After immunolabeling, tissue for electron microscopy was osmicated, dehydrated, embedded in plastic, sectioned, and counterstained.18 Light microscopy was used to select immunolabeled pyramidal cells from the CA1 region of the embedded section. These were then sectioned thinly and examined in a JEOL 100CX electron microscope.
Quantitation of Lesions
The number of lesions was quantified from images captured at x200 magnification using a Nikon Eclipse 800 light microscope coupled to a Photometrics SenSys digital camera. In hippocampus, three fields (0.153 mm2/field) from each region of Ammon's horn (CA1–4) were counted using the Metamorph Imaging System. In neocortical samples, three fields per case were counted in each of Layers III and V. After each field was captured, the stage was moved manually to a new field using fiduciary landmarks to ensure a completely nonredundant evaluation. The location of each field was further verified by maintaining a record of stage coordinates for each field examined.
Tissue Homogenates
Aliquots of fresh-frozen hippocampus were thawed, dissected to yield the CA1 sector, and snap-frozen in dry ice/ethanol for storage before homogenization. Samples of CA1 (30–200 mg) were suspended in 10 volumes (v/w) of 50 mmol/L Tris, pH 7.4, 50 mmol/L NaF, 1 mmol/L phenylmethylsulfonyl fluoride, 5 µg/ml leupeptin, and 1 mmol/L dithiothreitol and homogenized with 10 passes in a motor-driven glass-Teflon homogenizer. Aliquots of homogenates were immediately subjected to boiling in sodium dodecyl sulfate-polyacrylamide gel electrophoresis sample buffer.
Analytical Methods
The protein content of monoclonal antibodies was estimated spectrophotometrically, whereas brain homogenates were estimated by the method of Bradford.9 Levels of CK1 isoforms in tissue homogenates were estimated by Western analysis as described previously.9 Statistical errors are reported as ± one SD.
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Results |
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Three monoclonal antibodies were used to characterize the
distribution of CK1 isoforms in human brain: IC94.1, raised against
Cki; IC128A, raised against Cki; and 40250, raised against
Cki.9,19
The specificities of IC94.1 and IC128A were
shown previously,9
whereas that of 40250 is shown in
Figure 1
. These data confirm that 40250
reacts on Western blots with Cki but not with Cki, 3, or .
In homogenates of human neocortex, cerebellum, and brain stem, Cki
immunoreactivity appeared as a single species migrating close to its
calculated molecular mass (47.3 kd).19
This is in contrast
to Cki, which appears as three distinct species derived from
alternative splicing of a single gene. On the basis of quantitative
Western analysis, the levels of Cki as a percentage of total protein
(mean ± range) averaged 0.0032 ± 0.0004% (w/w). Thus
Cki, like other CK1 homologues examined to date, is widely
distributed within human brain at concentrations similar to those of
Cki.9
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To examine the cellular distribution of CK1 isoforms in human
brain, free-floating sections of temporal lobe were subjected to
immunohistochemical analysis with each of the three anti-CK1 antibodies
described above. First, the distribution in aged, nondemented control
temporal lobe was established. The results revealed that Cki had the
most selective localization of the three CK1 isoforms examined, being
highly enriched in the bodies of pyramidal neurons (Figure 2A)
. Thus, although the total brain
concentration of Cki is only threefold greater than that of
Cki,9
the neuronal concentration is probably much
higher, owing to neuron-selective distribution. In contrast, Cki
staining was widespread in gray matter, with immunoreactivity appearing
in both cell bodies and the neuropil (data not shown). Thus, despite
being nearly identical to Cki in primary structure within the
protein kinase catalytic domain,19
these two CK1 isoforms
appear differentially distributed in human brain. The final isoform,
Cki, showed the broadest distribution of the three, being found in
all areas of the section. No selective localization was apparent (data
not shown).
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To determine whether CK1 isoforms colocalized with fibrillar
pathology in AD brain, as predicted by their copurification with tau
filaments,9
sections of neuropathologically confirmed AD
temporal lobe were examined immunohistochemically. We focused initially
on neocortical regions (eg, superior temporal gyrus) because these
develop extensive fibrillar pathology in AD but not in aged,
nondiseased controls.20
The results showed that all three
CK1 isoforms examined colocalized with fibrillar pathology in this
region. Staining was most intense in layers III and V, with NPs
predominating in the former and NFTs in the latter (shown for Cki
only; Figure 2, B and C
). Approximately 63% of thioflavin-S-positive
NPs and 90% of thioflavin-S-positive NFTs contained anti-CK1
immunoreactivity in these layers (shown for Cki only; Figure 3
). Typically, NPs stained more intensely
than either neuropil threads or NFTs. The latter gave the greatest
variability, with some NFTs being strongly immunostained while others
stained only weakly. Overall, the staining pattern observed for each of
the anti-CK1 monoclonal antibodies closely resembled that of Tau2, a
monoclonal antibody that selectively recognizes filamentous
tau.11,12
|
; Figure 2D
).
Immunoreactive granules were large (up to 4 µm in diameter) and
reacted with all three anti-CK1 monoclonal antibodies described above
but not with Tau2. On closer inspection, the granules appeared to lie
within cytoplasmic vacuoles (shown for Cki and Cki; Figure 2, E and F
). The general appearance of these lesions resembled that of
granulovacuolar degeneration (GVD), a feature of AD pathology
characterized by the accumulation of granule-bearing vacuoles of
characteristic size, morphology, and intrahippocampal
distribution.1 CK1 Isoforms Colocalize with GVD Bodies
On the basis of four criteria, CK1 isoforms are biochemical
markers for GVD. First, the intracellular distribution of authentic GVD
bodies, as detected by the classic procedure of hematoxylin and eosin
histology, correlate with CK1 immunostaining in serial, 6-µm-thick
paraffin-embedded coronal sections of hippocampus (shown for Cki;
Figure 2, G and H
). Both methods detect granule-bearing vacuoles of
characteristic size and perinuclear distribution. Second, the
intrahippocampal distribution of CK1-positive bodies follows the
pattern established for GVD,21,22
with the greatest number
of involved neurons lying within the CA1 region of Ammon's horn,
followed by CA2 and CA3/CA4 (shown for Cki and Cki in Figure 4
). Although present in aged, nondemented
controls, these lesions are encountered far less frequently than in the
AD group (Figure 4)
. Third, CK1-positive granules retain the
ultrastructure of GVD bodies,1
consisting of coarse,
electron-dense granules in the center of large cytoplasmic vacuoles
(shown for Cki; Figure 5A
). Labeling
of these structures with colloidal gold confirmed that Cki is
localized primarily within the matrix of the vacuole (Figure 5B)
.
Finally, CK1-positive bodies, like those observed in authentic GVD, are
large (see above; Figures 2 and 5
), having three to five orders of
magnitude larger volume than normal intracellular bodies such as
endosomes or lysosomes.23
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The pattern of immunoreactivity described above for Cki, ,
and suggests these enzymes are selectively enriched in both
fibrillar and granulovacuolar lesions of AD. Yet these same lesions are
rich in phosphoepitopes and cross-react strongly with monoclonal
antibodies that recognize phosphate moieties as part of their epitope
selectivity.24,25
Although it has been shown that the
monoclonal antibodies used to detect Cki, , and are
monospecific for each protein kinase isoform and do not cross-react
with other phosphoproteins on Western blots of crude brain
extracts9
(see Figure 1
), it is still possible that
phosphate moieties mediate the association of the monoclonal antibodies
with each CK1 isoform studied. Therefore, the differences in CK1
immunoreactivity observed in AD and control tissue could reflect
protein kinase phosphorylation (eg, arising from changes in trans- or
autophosphorylation) rather than changes in the levels of protein
kinase polypeptides. To examine this possibility, tissue sections were
preincubated with or without alkaline phosphatase (an enzyme that
hydrolyzes phosphoepitopes found in NFT)16,26
before
immunostaining with anti-CK1 monoclonal antibodies. The efficacy of the
treatment is shown in Figure 6
. In the
absence of phosphatase pretreatment, tissue sections derived from AD
brain stained poorly with monoclonal antibody Tau1 (Figure 6A)
.
Pretreatment with alkaline phosphatase, however, removed covalently
bound phosphate and unmasked the Tau1 epitope (Figure 6B)
.16
In contrast, alkaline phosphatase pretreatment did
not attenuate the ability of anti-CK1 antibodies to react with either
fibrillar or granulovacuolar lesions (shown for Cki only in Figure 6, C and D
). Combined with the monospecificity illustrated in Figure 1
,
these data suggest that the monoclonal antibodies used in this study do
not bind CK1 isoforms through phosphoepitopes and that the large
increases in anti-CK1 immunoreactivity seen in AD tissue reflect
increased levels of CK1 polypeptides in disease.
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To confirm that levels of Cki, , and increase in AD,
each isoform was quantified by Western analysis of tissue homogenates
prepared as described in Materials and Methods. The CA1 region of
hippocampus was chosen for analysis because it is a rich source of both
GVD and fibrillar pathologies.27
As shown in Figure 7, A–C
, the results confirm that the
strong immunohistochemical staining of individual CK1 isoforms in AD
hippocampus results from elevations in the amounts of these protein
kinases, not from cross-reactivity with other cell consituents.
Quantitation of Western blots revealed elevations in CK1 levels ranging
from ~2.4-fold for Cki to about ninefold for Cki to ~33-fold
for Cki (Figure 7E)
. In contrast, levels of type IIIß tubulin, a
neuron-specific form of tubulin,10
did not differ between
the AD and age-matched control groups (Figure 7, D and E)
. Together,
these data suggest that the CK1 family of enzymes, in particular the
Cki isoform, is greatly elevated in AD and associated with
neurofibrillary and granulovacuolar lesions.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, , and are greatest in GVD bodies, followed by NPs,
followed by NFTs. In the former lesion, CK1 isoforms are sequestered
from the neuronal cytoplasm within the matrix of vacuoles. In
neurofibrillary lesions, CK1 isoforms are positioned appropriately to
mediate tau hyperphosphorylation, a reaction they catalyze in
vitro.28
The association between CK1 and tau
filaments appears to be physical, as it is maintained through stringent
purification methods.9
As a result, at least one CK1
isoform, Cki, is a major co-isolate of purified tau filaments,
comprising as much as 0.5% (w/w) of immunopurified preparations.
Normally, Cki, , and are relatively low-abundance enzymes,
differentially distributed in brain and ranging from 0.002–0.003%
(w/w) of total cellular protein.9
With the appearance of
AD pathology, however, CK1 levels increase markedly, with one isoform,
Cki, rising >30-fold in the CA1 sector of Ammon's Horn. This is
the first demonstration of a phosphotransferase being elevated by an
order of magnitude in authentic AD tissue. It will be important to
assess whether these increases result from changes in transcriptional
regulation or from changes in protein turnover and whether they are
accompanied by increases in CK1 activity. On the basis of
immunohistochemical localization, the increase in protein kinase levels
parallels the appearance of AD-related lesions.
Other links between GVD bodies and tau filaments have been proposed previously. Chief among these are tau and neurofilament proteins.24,29 Yet despite clear evidence for tau protein in neurofibrillary lesions, its presence in GVD bodies is controversial. Although some monoclonal antibodies raised against PHF-tau label GVD bodies strongly,24,25 it has not been possible to identify tau or neurofilament peptides directly in these lesions.30 On the contrary, it appears that these antibodies are capable of cross-reacting with phosphoepitopes found within unrelated phosphoproteins,16 and that neither tau- nor neurofilament-derived polypeptides are abundant in GVD bodies.30 In contrast, we have shown that CK1 immunoreactivity is not mediated by phosphoepitopes and that the appearance of GVD and neurofibrillary lesions is accompanied by major increases in the amounts of these protein kinases. Because of their location, the CK1 isoforms identified here may play a role in generating the abundant phosphoepitopes found in both GVD and neurofibrillary lesions.
Another protein found consistently in NFTs and NPs,31 and frequently in GVD,30 is ubiquitin. The physiological importance of the latter observation is unclear, as ubiquitin is a key component of proteosome-mediated proteolysis32 unrelated to the autophagic lysosomal pathway thought to underlie GVD body formation.33 Autophagy is distinguished from other degradative processes in that it involves cytoplasmic sequestration and employs a modification cascade distinct from the ubiquitin pathway.34 Yet because it functions by a relatively nonselective volume uptake mechanism, most organelles and macromolecules are subject to vacuolar isolation in proportion to their cytoplasmic abundance. This may account for the inconsistent presence of ubiquitin in GVD bodies.
Similarly, the association of CK1 isoforms with GVD bodies and tau
filaments reported here may reflect their abundance within degenerating
neurons or nonspecific trapping within proteinaceous aggregates. Yet
the high levels of CK1 found in these lesions, coupled with the
emerging biological functions of CK1, suggests both associations may be
of regulatory significance. First, the budding yeast homologue of
Cki, the CK1 isoform most upregulated in AD hippocampus, functions
as a negative regulator of vesicle budding from the endoplasmic
reticulum.35
Thus, Cki is positioned to participate in
the pathological formation of GVD bodies, which are enclosed by
membranes morphologically related to and potentially derived from the
endoplasmic reticulum. Second, overexpression of CK1 isoforms in
budding yeast can suppress trafficking defects arising from null
mutants of guanine nucleotide-binding proteins or their
effectors.36
Although particulate forms of CK1 are
normally essential for budding yeast viability, their loss can be
complemented by null mutations in adapter proteins associated with
clathrin-mediated transport.37
Together these data
implicate roles for CK1 homologues in the modulation of intracellular
trafficking and participation in transport-dependent cellular processes
such as autophagy, secretion, and phagocytosis. Other phenotypes
associated with CK1 in lower eukaryotes, including control of DNA
repair,38
cell morphology,39
and circadian
rhythm,40,41
may result indirectly from their role in
intracellular transport. For example, DNA repair defects can result
from impaired protein turnover.42
Although the precise molecular mechanism by which CK1 isoforms modulate
trafficking is unknown, the intracellular distribution of CK1 isoforms
investigated to date suggests they exert their effects at the level of
the cytoskeleton. First, in cycling cells, Cki colocalizes with both
the mitotic spindle and the centrosome, revealing that this isoform has
access to at least a subpopulation of microtubules before filament
formation.43
Second, Cki copurifies with neurofilament
proteins, suggesting a direct interaction with these cytoskeletal
proteins in situ.44,45
Third, deletion of
Cki homologues in fission yeast results in enhanced sensitivity to
benomyl, a microtubule depolymerization agent.46
These
data suggest that interaction with the cytoskeleton is a normal
function of some CK1 isoforms.
Members of the CK1 family of protein kinases share a common structure
and enzymology, suggesting they serve a similar function in different
contexts.47,48
Each of the three isoforms investigated
here colocalizes with intracellular AD pathology and retains the unique
phosphate-directed substrate selectivity characteristic of family
members.9
Yet the data presented here suggest that Cki
is the isoform most closely linked with the appearance of AD pathology.
First, its levels are dramatically elevated in AD versus
normal control tissue, rising over 30-fold. In contrast, increases in
Cki levels averaged only 2.4-fold. Second, Cki is selectively
localized to neuronal populations in normal tissue, unlike Cki and
Cki, which appear widely distributed. Third, its function as
currently defined in model systems is associated with trafficking
events occurring at the endoplasmic reticulum. Although the gene
encoding Cki maps to 17q25,49
in the vicinity of the
locus for frontotemporal dementia with parkinsonism, chromosome 17 type
(17q21–22),50
no familial frontal lobar atrophies have
been linked to Cki.
A hypothetical model for a role of CK1 in AD pathogenesis is presented
in Figure 8
. We propose that breakdown of
the microtubule cytoskeleton51
beginning in early stage AD
leads to disruption of motor-driven intracellular
transport52
and results in loss of functionality of
intracellular organelles such as endoplasmic reticulum and the Golgi
apparatus.53,54
Increased CK1 levels, particularly of
Cki, may be a physiological response of neurons to suppress these
trafficking defects in AD, much as they do in lower
eukaryotes.35
Elevated levels of CK1 could then
hyperphosphorylate substrates at their point of action, the
cytoskeleton. Because hyperphosphorylation of tau leads to microtubule
dissolution,51
which in turn can produce Golgi
fragmentation and other trafficking defects,52,54
elements
of a pathological positive feedback loop are in place. The population
of neurons affected may dictate whether the product of the loop is
manifested primarily as neurofibrillary or granulovacuolar
degeneration.
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Acknowledgements |
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Footnotes |
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Supported by grants from the National Institutes of Health (AG09466, AG14452, GM56292) and the Alzheimer's Association (RG2–29-076).
Accepted for publication June 3, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(CSNK1D) gene and its chromosomal localization. Genomics 1996, 32:140-143[Medline]
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