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Next Article 
The Journal of Neuroscience, April 15, 1998, 18(8):2801-2807
Ectopic Cell Cycle Proteins Predict the Sites of Neuronal Cell
Death in Alzheimer's Disease Brain
Jonathan
Busser,
David S.
Geldmacher, and
Karl
Herrup
Alzheimer Research Laboratory, Department of Neurology, Case
Western Reserve University, School of Medicine, Cleveland, Ohio 44106
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ABSTRACT |
Alzheimer's disease (AD) is a major dementing illness
characterized by regional concentrations of senile plaques,
neurofibrillary tangles, and extensive neuronal cell death. Although
cell and synaptic loss is most directly linked to the severity of
symptoms, the mechanisms leading to the neuronal death remain unclear.
Based on evidence linking neuronal death during development to
unexpected reappearance of cell cycle events, we investigated the
brains of 12 neuropathologically verified cases of Alzheimer's disease and eight age-matched, disease-free controls for the presence of cell
cycle proteins. Aberrant expression of cyclin D, cdk4, proliferating
cell nuclear antigen, and cyclin B1 were identified in the hippocampus,
subiculum, locus coeruleus, and dorsal raphe nuclei, but not
inferotemporal cortex or cerebellum of AD cases. With only one
exception, control subjects showed no significant expression of cell
cycle markers in any of the six regions. We propose that
disregulation of various components of the cell cycle is a
significant contributor to regionally specific neuronal death in
AD.
Key words:
Alzheimer's disease; cell death; cyclin D; cyclin B1; PCNA; cdk4
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INTRODUCTION |
Alzheimer's disease (AD) is the
major cause of dementia in older adults. The prevalence of the disease
increases with age, from ~1% at age 60 to nearly 50% by age 85 (Evans et al., 1989 ). Clinically, AD is characterized by a progressive
decline in cognitive abilities accompanied by behavioral abnormalities.
Average survival after disease onset is ~8 years (Jost and Grossberg,
1995). In neuropathological examinations, the most common abnormalities are unusually high densities of senile plaques and neurofibrillary tangles predominantly in hippocampus and entorhinal cortex, with lower
densities elsewhere (Alzheimer, 1907; Blessed et al., 1968). In
addition to the plaques and tangles, there is evidence of significant neuronal cell death, also with distinct regional variability. In some
regions, such as hippocampus, the cell loss occurs in conjunction with
high densities of plaques and tangles. In other regions, neuronal death
is found but the density of plaques and tangles is low. Examples of
this latter situation are the basal forebrain (Whitehouse et al., 1982)
and in nuclei of the brainstem such as the dorsal raphe and
locus coeruleus (Bondareff et al., 1982; Zweig et al., 1988).
The biological causes of neuronal cell death have been the object of
intense study in recent years. One intriguing finding has been evidence
linking the loss of cell cycle control with the occurrence of
programmed neuronal cell death during development. The first evidence
for this linkage arose from studies in transgenic mice in which cell
division was artificially induced in postmitotic neurons. (al-Ubaidi et
al., 1992; Clarke et al., 1992; Feddersen et al., 1992; Jacks et al.,
1992; Lee et al., 1992, 1994). Substantial neuronal loss was observed
in each instance, and the interpretation of these findings, as
articulated by Lee et al. (1992), is that once a neuron is born it has
made a commitment to maturation that includes a permanent cessation of
cell division. If for any reason it is forced to reenter the cell cycle
after this commitment, it dies. More recently, our laboratory has
extended this observation with evidence that naturally occurring
(target-related) neuronal cell death involves a reexpression of several
cell cycle markers, including DNA synthesis (Herrup and Busser, 1995).
Other authors have reached similar conclusions based on both in
vivo and in vitro studies (Heintz, 1993; Freeman et
al., 1994). The current study is an exploration of whether a similar
linkage between cell cycle events and cell death might exist in the
adult brain as well as in developing systems. There are virtually no
known CNS cancers that are neuronal in origin, a finding that is a
direct prediction of the cell cycle-cell death hypothesis.
Furthermore, there have been recent reports of the unexplained
reappearance of mitotic cyclins and their associated kinases in neurons
of the AD brain (Pope et al., 1994; Liu et al., 1995; Vincent et al.,
1996, 1997). From their evidence, Vincent et al. (1997) conclude that
the disregulation of cdc2 kinase activity leads to tau
hyperphosphorylation and the neurofibrillary tangle pathology of
AD.
We report here additional evidence that lends credence to the
hypothesis that ectopic expression of cell cycle proteins is a central
event in the neurodegeneration in AD. Specifically, we found an
abnormal appearance of the cell cycle markers cyclin B1, proliferating
cell nuclear antigen (PCNA), cdk4, and cyclin D in regions where cell
death is extensive. In each region we examined, there was a good
correlation between the presence of cell cycle markers and neuronal
loss. In contrast, immunohistochemical evidence for neurofibrillary
tangles was associated with neuronal death only in hippocampus and
entorhinal cortex. Comparison of the relative density of cells that are
positive for the various cell cycle markers suggests a model in which
the normal cascade of cell cycle enzymes begins normally but then
disregulates. The resulting disruptive effects are proposed to be the
mechanism that ultimately leads to neuronal loss in the brains of AD
patients.
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MATERIALS AND METHODS |
Tissue. Human autopsy brain tissue was obtained from
the Alzheimer Disease Research Center at Case Western Reserve
University. All 12 AD cases were confirmed pathologically. The tissue
had a median postmortem interval (between death and autopsy) of 5 hr,
ranging from 1 to 8 hr (Table 1,
Alzheimer's). Our eight age-matched controls were pathologically
verified as disease-free and had postmortem intervals from 3 to 22 hr
with a median time of 10.25 hr (Table 1, Normal). Brains were
immersion-fixed for a minimum of 14 d in 20% formalin. A listing
of the various cases used in this study can be found in Table 1. Tissue
samples were embedded in Paraplast+ (Fisher Scientific, Pittsburgh, PA)
and sectioned at 10 µm on a Leitz (Wetzlar, Germany) 1512 microtome. The sections were deparaffinized in xylene and rehydrated through graded ethanols to water.
Antibodies. The PCNA mouse monoclonal antibody (SC-56; Santa
Cruz Biotechnology, Santa Cruz, CA) recognizes the PCNA p36 protein in
a broad variety of species. The monoclonal cell line that produces it
was described by Waseem and Lane (1990). Cyclin B1 mouse monoclonal antibody (SC-245; Santa Cruz) is a mouse IgG prepared from spleen cells
of mice immunized with recombinant human cyclin B1. Cyclin B1 is a
regulatory subunit of the cdc2 protein kinase that is believed to
initiate mitosis (Doree, 1990). A rabbit polyclonal antibody to cyclin
B1 (Santa Cruz) was also used on some material. The cyclin D (06-137)
and cdk4 (06-139) were obtained from Upstate Biotechnology (Lake
Placid, NY). Both are rabbit polyclonal antibodies prepared against
C-terminal regions of the human proteins. The TG3 antibody recognizes
phosphorylated epitopes of the paired helical filaments (PHFs)
characteristic of Alzheimer's disease (Vincent et al., 1996). The
PHF-1 antibody was raised against gel-purified PHF protein from AD
tissue (Greenberg et al., 1992). Both the TG3 and the PHF-1 antibodies
were generous gifts from Dr. Peter Davies (Albert Einstein College of
Medicine, Bronx, NY). Primary antibodies were visualized using the
Vectastain ABC Elite kit that uses peroxidase to produce a brown
diaminobenzidine reaction product. In cases in which double
immunolabeling was required, the Vectastain ABC-AP kit was used in
which alkaline phosphatase conjugated reagents to produce a red
reaction product when treated with the Vector Red substrate kit. All
kits were from Vector Laboratories (Burlingame, CA).
Immunohistochemistry. Deparaffinized sections were soaked in
3% hydrogen peroxide to remove endogenous peroxidase activity and then
rinsed five times in PBS. All Santa Cruz and Upstate Biotechnology
primary antibodies were used at a 10 µg/ml concentration in PBS
containing 20% goat serum and 0.5% Tween 20 and applied to the
sections overnight at room temperature in a humid chamber. The TG3 and
PHF-1 antibodies were used at various concentrations (1:10-1:1000)
with no effect on staining pattern. After overnight incubation, the
sections were washed four times in 100 mM Tris-buffered saline (TBS) before application of the secondary antibody (diluted 1:400). Sections were incubated for 1 hr in a humid chamber at room
temperature and then rinsed four times in TBS. For diaminobenzidine (DAB) localization, rinsed sections were incubated in Vectastain ABC
Elite reagent for 1 hr at room temperature. After three successive washes, the sections were incubated in 0.05% DAB (Polysciences, Warrington, PA) and 0.005% H2O2 in TBS for 5 min. The sections were then rinsed three times in PBS.
If the sections were to be double-stained, they were subsequently
incubated in 2N HCl for 20 min to strip the first primary antibody from
the tissue. After 10 PBS rinses, the sections were incubated in the
second primary antibody overnight as above. After four TBS rinses, the
sections were incubated in secondary antibody from the ABC-AP kit for 1 hr as above. They were then rinsed four times in TBS and incubated in
the ABC-AP reagent for 1 hr as above. After three successive rinses in
TBS, the sections were incubated in Vector Red substrate for 5-30 min
to visualize the second primary antibody.
All sections were counterstained in quarter-strength hematoxylin.
Morphometry. In the hippocampus, four AD and three normal
cases were counted to yield the results reported in Table
2. Cells were counted in three to five
sections from each region. First, the total number of
immunopositive cells was counted. A cell was scored only if it
contained clear evidence of immunostaining (peroxidase-DAB or alkaline phosphatase-Vector Red) and a visible nucleus. To determine the percentage of positive cells, all neurons were
counted in a single hematoxylin-stained section from a given region
(e.g., hippocampal pyramidal cell layer or locus coeruleus). Again, for a neuron to be scored as positive, a visible nucleus had to be present.
This total number was then used as a denominator to determine the
fraction of positive cells in each of several nearby immunostained sections. The resulting percentage will contain small errors
attributable to variations from section to section in the total number
of cells. Counts of additional hematoxylin-stained sections suggest
that this error is <10%.
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RESULTS |
Cell cycle markers in the hippocampus
Previous work on target-related cell death in mouse development
(Herrup and Busser, 1995) led us to search for the expression of cell
cycle proteins in at-risk populations of neurons in AD brains. We first
examined the hippocampus, which is affected early in the disease and
which has been extensively studied. We stained the tissue for the four
cell cycle markers: cyclin D, cdk4, PCNA, and cyclin B1.
As shown in Figure 1, the hippocampus of
affected individuals contains large pyramidal neurons with high levels
of expression of cyclin D (Fig. 1C). The open
circles in Figure 3 offer a sense of the distribution of these
cells in the hippocampus of two representative AD cases. Antibody
staining of cdk4 (Fig. 1D; see Fig. 3B,
filled circles) was also found. Although we examined 72 sections of hippocampal tissue from nondemented control tissue, we
found no cells labeled with the cyclin D antibody (Fig.
1E). Within the AD brain, we detected a reproducible
variation among the various CA fields (see Fig. 3); labeled cells were
predominant in the CA1 and CA3/4 areas of the hippocampus (the same
areas preferentially affected by cell loss in AD). Although labeled
cells were easily found in our material, overall only a tiny minority
of cells were cyclin D-positive in any one case. In the 10 AD cases we
examined, an average of 0.6% of the hippocampal cells were cyclin D
positive (see Fig. 3, open circles, Table 2).
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Figure 1.
Top. AD hippocampus stained for cell
cycle markers PCNA (A), cyclin B1
(B), cyclin D (C), and cdk4
(D). E, Similar field in a nondemented,
age-matched control brain stained for PCNA. The small arrows
indicate cells positive for the respective cell cycle marker. In
D, the larger arrow points to a TG3-positive
neuron that is cdk4-negative. Scale bars: 50 µm; C, inset,
20 µm.
Figure 2.
Bottom. Dorsal raphe nucleus stained for
cell cycle markers PCNA (A), cyclin B1 (B),
cyclin D (C), and cdk4 (D). E,
Representative field from a normal brain showing the lack of cyclin B1
staining. Other symbols as in Figure 1. Scale bar, 50 µm.
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The appearance of cyclin D (in complex with cdk4) is an early event in
a normal cell cycle (for review, see Nurse, 1990; Maller, 1991; Pines,
1993, 1994, 1995). We also asked whether later cell cycle markers were
present. Neurons known to be at risk in AD tissue consistently stained
with antibodies to both PCNA (normally an S phase protein; Figs.
1A,
2A) and cyclin B1
(elevated from G2 into mitosis; Figs. 1B,
2B). AD hippocampus stained well with both markers
(~9% positive cells; Table 2), yet when we examined control tissue,
little staining was found ( 0.5% positive cells). As with cyclin D
and cdk4, the majority of neurons that were positive for PCNA or cyclin
B1 were in the CA1 and CA3/4 regions of the hippocampus (Fig.
3, open triangles, open
squares, respectively). We also examined the subiculum of the
entorhinal cortex, which is a region of extensive cell loss in AD. We
found many examples of cells stained for all four cell cycle markers
tested either separately or in pairs (data not shown). Although cyclin
D always appeared in cell nuclei in our material, the subcellular
location of cyclin B1 and PCNA was most often cytoplasmic. For PCNA
this may be attributable to the use of paraformaldehyde rather than organic fixatives in the brain fixation protocol. Nonetheless, the
unusual location also hints that the regulation of these cell cycle
proteins may be somewhat aberrant in the stained AD neurons.
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Figure 3.
Camera lucida drawing of the hippocampus from two
AD cases. A, Case 92-447. The triangles
show the location of cells that were positive for PCNA staining in
three sections (combined on the outline of one). Likewise, the
squares show the results of staining for cyclin B1 from
three sections, and the open circles show staining from
five sections for cyclin D. B, Case 93-221. The symbols
are the same with each, representing positive cells in three sections.
This case was also stained for cdk4, represented by filled
circles. The arrows point to the locations of
the representative cells shown in Figure 1. In each figure, the various
CA fields are labeled as indicated. DG,
Dentate gyrus. Scale bar, 50 µm.
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Cell cycle markers in the brainstem and other regions
Another area of cell death in AD is the dorsal raphe nucleus. The
raphe lies just ventral to the locus coeruleus and loses nearly 50% of
its neurons in Alzheimer's disease (Zweig et al., 1988). When the
dorsal raphe was stained for cell cycle markers, only a few cells
stained positive for cyclin D (Fig. 2C), although somewhat
more stained for cdk4 (Fig. 2D). Approximately 10%
of the raphe neurons were positive for PCNA (Fig.
2A), with an equal percentage positive for cyclin B1
(Fig. 2B). Table 3
lists the percentage of positive cells in the raphe of AD and control
brains. The percentage of cells labeled with cdk4 is relatively high
compared with cyclin D. This might be attributable to the fact that the main regulation of cdk4 is via its phosphorylation state rather than
the absolute levels of protein. We found little immunostaining of
our control tissue. As in the other regions described above, there was
a near total lack of staining in nondemented control brains (Fig.
2E).
The locus coeruleus (LC) is another area decimated by cell death in AD
and is found in the rostral brainstem dorsal to the raphe. Zweig et al.
(1988) report that nearly 60% of these large pigmented noradrenergic
cells are lost in AD. When we looked for cell cycle markers in this
area, we found staining of all four markers used above: PCNA (Fig.
4A), cyclin B1 (Fig.
4B), cyclin D (Fig. 4C), and cdk4 (Fig.
4D). Although the melanin granules appear brownish
black in our staining reactions, the melanin pigmentation is easily
distinguished from the redder brown of the DAB reaction (Fig.
4C). Furthermore, the presence of the melanin in the
antigen-positive cells unequivocally identifies them as neurons.
Consistent with our findings in the hippocampus and the raphe, few
cells labeled with antibodies to cyclin D, whereas ~10% of the cells
labeled with the markers PCNA or cyclin B1 (Table
4).
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Figure 4.
Top. AD locus coeruleus stained for
cell cycle markers PCNA (A), cyclin B1
(B), cyclin D (C), and cdk4
(D). E, Representative field from a normal
brain showing the greater number of cells as well as the lack of
staining for PCNA. The arrows indicate cells positive for
the respective cell cycle marker. All antigens, except cyclin B1, were
revealed using the DAB reaction product (see Materials and Methods).
B, The cyclin B1 antigen was revealed using the Vector Red
reaction product (see above). C, The asterisk
points to a labeled non-neuronal cell, most likely a microglial cell.
Scale bars: A, B, D, E, 50 µm; C, D, inset, 20 µm.
Figure 5.
Middle. Double-stained sections for PHF-1
(red) and PCNA (brown) in the CA3/4 region of the
hippocampus (A), locus coeruleus (B), and dorsal
raphe nucleus (C). Note the double-labeling in the
hippocampus (A), whereas there is none (no PHF1-positive
cells) in representative fields of the LC or DR. Scale bar, 50 µm.
Figure 6.
Bottom. A, B, Sections of inferotemporal
cortex of AD (A) and normal (B) brains. The
sections were double-stained for PHF-1 (revealed with an alkaline
phosphatase antibody and red chromaphore) and the cell cycle
marker PCNA (revealed with a peroxidase antibody and the
brown, DAB chromaphore). Although many inferotemporal
neurons in both demented and control cases were PHF-1-positive, none
were positive for the cell cycle marker, PCNA. C, D, Sections of
cerebellum stained for PCNA. In both AD (C) and normal
(D) brains, there is no evidence of staining for the cell
cycle marker. Scale bar, 50 µm.
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The cerebellum is reportedly spared from most of the pathological
features of AD. Diffuse plaques were found but no neuritic plaques; no
tangles and little or no neuronal death were observed. We found no cell
cycle staining in any neuron in this region in either the AD cases or
the controls (see Fig. 6C,D).
We stained tissue for neurofibrillary tangles (NFTs) using either
PHF-1, an antibody raised against gel-purified PHFs from AD brain
(Greenberg et al., 1992) or TG3, an antibody that recognizes phosphorylated epitopes of tau, the main protein believed to make up
PHFs in AD (Vincent et al., 1996). Consistent with earlier reports,
when either of these antibodies was used alone, we found immunopositive
cells in CA1 and CA3/4 of the hippocampus, as well as in the subiculum
of the entorhinal cortex. Control tissue showed only a few positive
cells. To examine the expression of the cell cycle proteins in these
cells, we double-stained sections for NFTs and a cell cycle marker
(Table 2). Virtually 100% of PHF-1- or TG3-positive cells were stained
for PCNA in tissue from AD cases (Fig.
5A). Additionally, most
NFT-containing cells were also stained for cyclin B1. Significantly,
however, we found no examples of a cell double-labeled for a PHF marker
plus either cyclin D or cdk4, both of which are early cell cycle
proteins.
The inferotemporal cortex, anatomically close to the hippocampus and
entorhinal cortex, is well known for its high density of NFTs (Braak
and Braak, 1991, 1995) and neurons that are PHF-1-positive. When we
stained our cases with either of the two NFT markers, a relatively high
percentage of the neurons in this region were labeled (Fig.
6A). We observed no
apparent decrease in neuronal density, however, suggesting that despite
the presence of hyperphosphorylated tau protein, there was no extensive
neuronal loss. Consistent with this, we found no evidence of cell cycle
markers in this cortical region. Figure 6A is a
representative example of a group of cells in an AD brain that is
positive for TG3 (revealed with a red alkaline phosphatase reaction
product) but negative for cyclin B1 (which would have appeared brown).
Figure 6B is a section from a control case stained
with the same antibodies. Again, no cyclin B1 staining is apparent. In
contrast, in the hippocampus we found many examples of cells
double-labeled for a cell cycle marker and NFTs.
We also examined the expression of NFT markers in the brainstem.
Staining for either PHF-1 or TG3 yielded few positive cells in the LC
(Fig. 5B). This is consistent with earlier reports that show
few NFTs or senile plaques (SP) in the AD brainstem despite massive
cell loss (Zweig et al., 1988). Unlike the cells of the locus
coeruleus, a few raphe neurons were positive for NFT markers (Fig.
5C). This is also consistent with the findings of Zweig et
al. (1988) who reported 10-fold more neurofibrillary tangles in the
raphe than in the locus. PHF-1- or TG3-positive neurons were still
rare, however, especially when compared with the numbers seen in the
hippocampus.
One of the cases we included in our control group (case 94-139)
deserves additional comment. Although confirmed by neuropathological examination to be free of AD, her clinical history is suggestive of a
presymptomatic course of AD, including intermittent paranoid delusions
and acute delirium associated with her immediate premortem illness.
Extensive telephone interviews with her family, conducted 5 months
after her death from cardiovascular disease, revealed no significant
cognitive decline in the 5 years before her final illness. Despite not
meeting the neuropathological criteria for AD, our quantitative
evaluation revealed a significant (~30%) cell loss in locus
coeruleus (D. Geldmacher, J. Busser, and K. Herrup, unpublished
observations), as well as increased densities of NFTs and SPs in
hippocampus. Interestingly, we found increased cell cycle marker
expression in this case relative to our other nondemented controls in
all areas examined. Indeed, all of the cells positive for one of the
cell cycle markers reported in our control group (Tables 2-4) stem
from this one individual.
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DISCUSSION |
The results presented here represent a survey of proteins normally
present only during the cell cycle in the brains of individuals who
have died with Alzheimer's disease. Six regions have been examined in
detail: hippocampus, subiculum, locus coeruleus, dorsal raphe,
inferotemporal cortex, and cerebellum. In clinically affected individuals, neurons in the first four of these locations were depleted, and in each of these areas we found significant numbers of
cells that were immunopositive for one or more of the four cell cycle
proteins we studied: cyclin D, cdk4, PCNA, and cyclin B1. In contrast,
neurons in the same brain sites in nondemented, age-matched control
brains showed little to no evidence of immunoreactivity; staining was
not found in the regions of the Alzheimer's disease brain where no
exceptional cell death was identified. These findings argue for an
association between these cell cycle-related proteins and the death of
neurons in Alzheimer's dementia. This conclusion is further
strengthened by our observations in the larger neurons of
Ammon's horn and the subiculum where antibodies against
hyperphosphorylated tau are found co-localized with the cell cycle
components.
Our findings in hippocampus and subiculum confirm and extend the work
of Vincent et al. (1997), who reported both biochemical and
immunological evidence for the association of hyperphosphorylated tau
and cdc2, complexed with its regulatory subunit, cyclin B1, in AD but
not control brains. From the evidence it seems likely that in
susceptible cell populations the abnormal presence of the active form
of cdc2 is responsible, at least in part, for the hyperphosphorylation
of neuronal proteins such as tau. Although cdc2 is not directly
responsible for the PHF-1 epitope, our findings suggest that there must
be more to the story than tau phosphorylation alone. Specifically, in
cell groups such as the locus coeruleus and dorsal raphe, there is
massive cell death in Alzheimer's disease but little evidence of PHF-1
phospho-tau staining. In contrast, we have not identified any region of
the CNS where there is evidence of large-scale neuronal death in AD
without evidence of ectopic cell cycle components. These observations
lead us to propose that it is the unscheduled expression of the mitotic
proteins rather than the protein phosphorylation abnormalities per se
that is a requisite antecedent to neuronal loss in AD. This is
consistent with the results of experimental studies in developing mouse
brain and extends to the adult the hypothesis that if mature (or
maturing) neurons ectopically express the enzymes and regulatory
proteins of the cell cycle, they will die rather than divide.
Our quantitative investigations suggest additional aspects of the cell
death process. We find that the percentages of cyclin D-positive cells
are much smaller than the percentages of PCNA- or cyclin B1-positive
cells. In agreement with Vincent et al. (1997), we find no trace of
mitotic figures. In the normal cell cycle, cyclin D is elevated only
during late G1 phase; cdk4 levels rise during
G1 but remain high; PCNA is present only during S and early
G2 phases; and cyclin B1 is elevated only in G2
phase. Superficially, therefore, the cells we have observed in the AD brain would appear to have begun a "cycle" in which they finish G1 normally, only to become blocked in the later stages. In
truth, the term cycle is a misleading one here, because in a well
regulated cell cycle, PCNA levels should go down as cyclin B1 levels
rise. Furthermore, the localization of the PCNA and cyclin B1 proteins should be predominantly nuclear, although in our material they can be
either nuclear or, more commonly, cytoplasmic. For PCNA this may result
in part from the use of formaldehyde fixation (Bravo and
MacDonald-Bravo, 1987), but overall it seems that whereas the AD
neurons can begin a cascade of gene expression that includes various
cell cycle components, the tight coordination that characterizes a
normal cycle is soon lost. It would be of interest to learn whether DNA
replication was a part of this abnormal response, but such data are
unavailable at present.
The control case (94-139) in which early pathological signs of AD were
found provides strong, albeit anecdotal, evidence that the association
between the cell cycle markers and the presence of neuronal cell death
in AD is not simply a fortuitous one. Behavioral abnormalities in this
patient were exhibited only with provocation, and there was only modest
cell loss in all areas examined. These features, coupled with the
presence of an increased (if subcriterion) density of SP and NFT, would
argue for the possible categorization of this individual as one in the
early stages of the disease process. The correlated appearance of the
cell cycle markers strongly supports the proposition that this evidence
of ectopic reentrance into the cell cycle is not merely an
epiphenomenon associated with the end stage of the disease, but rather
an integral part of the entire disease process.
That 10% of the neurons in the hippocampus (or LC) of an AD patient
are positive for PCNA and/or cyclin B1 means that the death of these
cells must require considerable time after cyclin induction. This can
be compared and contrasted with the target-related death of neurons
during development. In an earlier study of two mouse models of cell
death, we demonstrated that cerebellar granule cells that are fated to
die reenter the cell cycle as a part of that process (Herrup and
Busser, 1995). As in the current study, we found evidence of abnormal
expression of cyclin D and PCNA in the neurons at risk. This suggests
that regulatory events associated with attempted but unscheduled
reentry into the cell cycle likely lead to neuronal cell death at
different points in the life span. During development, however, neuron
death is far more rapid. By administering the DNA precursor
bromodeoxyuridine (BrdU) at various times before killing the mice and
scoring the number of BrdU-labeled pyknotic cells, we were able to
determine that the time between the beginning of S phase and cell death
was ~10 hr (about one-half of a normal granule cell cycle). In
contrast, the observation of a 10% PCNA or cyclin B1 labeling
frequency, coupled with a disease progression that takes several years,
means that the human neurons must survive for several months before
succumbing. This suggests that the young neurons of the developing CNS
may be more vulnerable to cycling-induced death. It also implies that
the mature neurons of the aging human brain not only must be blocked in
their ability to divide, but they also seem to be more resistant to the
effects of the cell cycle-induced degeneration.
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FOOTNOTES |
Received Nov. 17, 1997; revised Jan. 20, 1998; accepted Jan. 28, 1998.
This work was supported by National Institutes of Health Grant NS20591
to K.H. and Neuropathology Core of the Case Western Reserve/University
Hospitals Alzheimer's Disease Research Center Grant AG08012. We extend
our gratitude to Dr. Peter Davies for his generosity in providing us
with the antibodies to the PHF-1 and TG3 epitopes.
Correspondence should be addressed to Dr. Karl Herrup, Alzheimer
Research Laboratory, Department of Neurology, Case Western Reserve
University, School of Medicine E504, 10900 Euclid Avenue, Cleveland, OH
44106.
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Abstract
Introduction
