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From the Department of Psychiatry,*
University of
Cambridge, Cambridge, United Kingdom; the Department of
Pathology,
Cambridge Brain Bank Laboratory,
University of Cambridge, Cambridge, United Kingdom; the Department of
Physiology,
Biophysics, and Neurosciences,
CINVESTAV-I.P.N., Mexico City, Mexico; the Department of
Psychiatry,§
University of Leipzig, Leipzig,
Germany; the Departments of Public Health and Primary
Care||
and the MRC Biostatistics
Unit,**
Institute of Public Health, University of
Cambridge, Cambridge, United Kingdom; the Laboratory of Molecular
Biology,
Medical Research Council
Centre, Cambridge, United Kingdom; the Department of
Psychiatry,
University of
British Columbia, Vancouver, Canada; and the Department of Mental
Health,§§
University of Aberdeen,
Aberdeen, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-synuclein and MAP2 at stage 4. Minimal
and mild clinical grades of dementia were associated with either
unchanged or elevated levels of synaptic proteins in the neocortex.
Progressive aggregation of paired helical filament (PHF)-tau
protein could be detected biochemically from stage 2 onwards,
and this was earliest change relative to the normal aging background
defined by Braak stage 1 that we were able to detect in the neocortex.
These results are consistent with the possibility that
failure of axonal transport associated with early aggregation of tau
protein elicits a transient adaptive synaptic response to partial
de-afferentation that may be mediated by trophic factors. This early
abnormality in cytoskeletal function may contribute directly to the
earliest clinically detectable stages of dementia.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have implemented this strategy in a community-based cohort of postmortem cases defined in the course of a prospective epidemiological study of cognitive decline in the aging population.1-3 To define the progression of AD in this sample empirically, we have developed analytical tools to measure a range of molecular changes in human postmortem brain tissues.4-11 Initial neuropathological investigations of these cases have been reported previously. We showed that 90% of the cases conformed to the neuropathological staging proposed by Braak and Braak,12 and that only 10% of the cases were at the extremes of pathology as represented by Braak stages 1 and 6. In the present study, we have combined neuropathological Braak staging with clinical staging during life as defined by CAMDEX13 to provide an empirical framework for staging the neurobiology of AD in human isocortex.
In the present study, we have sought to examine the sequence of changes affecting synaptic proteins in the association neocortex in relation to changes in the cytoskeleton and deposition of ß-amyloid plaques. The association neocortex provides a particularly useful anatomical substrate for this purpose. First, synapse loss in frontal and temporal neocortex has been proposed as the principal biological correlate of clinical dementia.14,15 Second, and much more important, neurofibrillary degeneration does not become prominent in these regions until Braak stages 5 and 6. Therefore, the changes occurring in neocortex at Braak stages 1 to 4 could provide an insight into early events in the neurobiology of AD before the later phases of neurofibrillary degeneration.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The brain tissue used in the present study was derived from 48
patients (33 women and 15 men) in the Cambridge Project for Later
Life.1-3
In addition to prospective clinical and
neuropsychological assessments, these individuals agreed to donate
their brain tissue for research purposes.16
They have been
fully characterized in earlier neuropathological studies (Table 1)
.17,18
The group consisted
of 14 individuals with no cognitive impairment, seven with a definite
diagnosis of cerebrovascular dementia,19
20 with AD, five
with mixed dementia,19
one with progressive supranuclear
palsy, and one with chronic delirium. Two cases from the 50 reported
previously17,18
were excluded from the present study
because of lack of frozen brain tissue samples.
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Tissue Sampling and Morphometric Analysis
At the time of limited autopsy, one cerebral hemisphere and the contralateral cerebellar hemisphere were fixed, whereas the remaining hemisphere was sliced into 1-cm-thick slices in the coronal plane and snap-frozen. The brain sampling was performed on these frozen sections, taking the gray matter of the association areas of the frontal (BA9 and BA10) and temporal (BA22 and BA23) neocortical areas. Uniformity of sampling was maintained by using internal neuroanatomical markers when taking tissue from the frozen slices, ie, head of caudate and the beginning of ventricles (for the frontal areas) and the junction between amygdala and hippocampus (for temporal and medial temporal lobe areas). Neuropathological staging was performed by two neuropathologists (JX and HG) according to the criteria of Braak and Braak.12 The morphometric analyses have been described previously.17,18 Sections (7-µm thick) were cut and stained with hematoxylin and eosin to assess nerve cell loss, gliosis, and ischemic change, whereas Congo red was used to assess vascular amyloid deposits. The Campbell silver staining method and immunohistochemistry with a monoclonal antibody against Aß (a gift from Dr. M. Landon, Nottingham University, Nottingham, UK), were used to demonstrate ß-amyloid deposits, and monoclonal antibody (mAb) 11.57 was used for labeling neurofibrillary pathology.
Biochemical Analysis and Enzyme-Linked Immunoassays (ELISA)
In all experiments, 0.3 g to 0.5 g of frozen brain tissue was used. The brain tissue was homogenized in 0.32 mol/L sucrose, and the homogenate divided into two equal portions. One portion was processed through the A68 protocol, containing the synaptosomal preparation, and the other through the if-II protocol as described.10
Phosphorylated Tau and Synaptosomal Protocol
After homogenization, an equal volume of 1 mol/L NaCl was added to the brain homogenate, and this material was centrifuged at 13,000 x g for 15 minutes. The supernatant was used for preparation of synaptosomes (containing synaptophysin, syntaxin, and SNAP-25), according to the protocol of Alford et al.20 The pellet was rehomogenized in 0.32 mol/L sucrose, and an equal volume of buffer containing 2 mol/L NaCl, 1 mmol/L MgCl2, 2 mmol/L EGTA, 0.32 mol/L sucrose, 200 mmol/L MES, (pH 6.5), was added, followed by centrifugation in a Beckman TL100 ultracentrifuge at 25,000 x g for 15 minutes at 4°C. The supernatant was removed and sarkosyl was added to a final concentration of 1%; the mixture was incubated with gentle rotation at 25°C for 1 hour. It was then centrifuged at 200,000 x g for 30 minutes at 4°C. The supernatant was discarded, and the pellet (A68) was retained for analysis of sarkosyl-insoluble phosphorylated tau protein.
PHF-Tau and Soluble Tau/MAP2 Protocol
The brain homogenate was centrifuged at 85,000 x g for 15 minutes. The supernatant was used to prepare the S1 fraction containing heat stable proteins as described previously.4,6,7 Soluble phosphorylated tau (mAb AT8) and synuclein (pAb PER2) immunoreactivity were measured in the S1 fraction. The pellet was suspended in 0.5 mol/L sucrose, centrifuged at 233,000 x g for 1 hour at 15°C. The pellet was resuspended in 0.5 mol/L sucrose again, and divided into two equal portions. Half was digested with Pronase (2 mg/ml final concentration) for 1 hour at 37°C. Both halves were then centrifuged at 233,000 x g for 1 hour. The pellets were suspended in 500 µl of NH4HCO3 (50 mmol/L, pH 8.0) and analyzed for PHF-tau content with mAb 423 (after Pronase digestion) or with mAbs 7.51 and AT8 (after formic acid treatment).10
Immunoassays
The levels of synaptophysin, syntaxin, and SNAP-25 were determined
using an indirect ELISA, with mAbs EP10 (1:10), SP8 (1:100), and SP12
(1:100), respectively. These antibodies have been characterized
previously21
and their immunoreactivity has been shown to
be independent of postmortem delay.22
The level of
synuclein was also determined in an indirect ELISA, using a polyclonal
serum PER2 (1:2,000) raised against the C-terminal portion of the
-synuclein molecule, and its characteristics have been described
previously.23
The level of MAP2 protein was determined
using a competitive ELISA, with a mAb C (1:2,000), 24
with
a synthetic peptide corresponding to MAP2c sequence (50 ng/ml) serving
as a solid phase (a gift from Dr. A. Matus, Freidrich Miescher
Institut, Basel, Switzerland). Each sample was analyzed in
triplicate at six dilutions, and assay curves were plotted using
Softmax, version 2.0 (Molecular Devices Corp., Sunnyvale, CA). All
values have been normalized for 0.3-ml fraction from 0.3 g to
0.5 g brain tissue and expressed as relative arbitrary units of
immunoreactivity.
Statistical Analysis
PHF-tau, phosphorylated tau, and pathological variables were
log-transformed before analysis [value = ln (value + 1)], as
these have been shown previously to increase exponentially with disease
progression.11
Synaptic protein markers and MAP2 were not
log-transformed. All variables were grouped either according to Braak
stage or CAMDEX clinical stage and analyzed according to a uniform
one-factor orthogonal matrix structure by classical analysis of
variance allowing for two repeated measures (frontal and temporal
region) per case. Values for mean square error, F,
P, mean difference, and 95% confidence interval of the
difference are tabulated. These analyses were supplemented by
one-sample t-tests to determine deviations of PHF-tau values
from zero in nondemented patients. In correlational analyses,
Pearson’s r was calculated for continuous data (PHF-tau
measures) and Kendall’s 
for correlations determined with respect
to categorical variables (Braak stage and clinical severity). The
analysis of variance analyses were undertaken using the Unistat Version
3 statistical package (Unistat Ltd., UK), and other
supplementary analyses used SYSTAT-6 for Windows (SPSS, Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As expected, association neocortex was essentially free
of neurofibrillary tangles, -immunoreactive neuritic plaques and
neuropil threads at Braak stages 1 to 3. Likewise, no significant
changes in counts of ß-amyloid plaques were detected at stages 1 to
3. The significant increase in ß-amyloid plaques and the whole
spectrum of -reactive pathology were first observed at stage 4
(Figure 1
; Table 2
). Therefore, histological involvement
of association neocortex is relatively late in terms of the classical
histological hallmarks of AD.
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To determine whether staging based on the progression of pathology
outside the neocortex at Braak stages 1 to 4 predicted tau protein
changes occurring in the neocortex at these stages, we examined three
different measures of PHF-tau accumulation that we have used
extensively in previous studies. These were: mAb 7.51 immunoreactivity
after formic acid treatment, mAb AT8 immunoreactivity in the PHF
fraction prepared without Pronase, and mAb 423 immunoreactivity in the
PHF fraction prepared with Pronase.10,11
These parameters
were highly correlated (0.73 < < 0.84). Statistically
significant increases in all three parameters were first detected at
stage 2, and this increased exponentially with respect to stage
thereafter (Figure 2
; Table 2
). All
PHF-tau markers were significantly correlated with stage (0.47 <
< 0.50). Therefore, Braak staging correctly predicts the
accumulation of PHF-tau in neocortex well before the appearance of
visible histological changes in tau immunoreactivity.
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, whereas that in the
soluble fraction did not change until stage 6 (Figure 3
; Table 2
). Therefore, significant
increases in non-PHF-bound forms of hyperphosphorylated tau protein
appear at least two Braak stages after the onset of insoluble PHF-tau
accumulation in the human brain.
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In the light of discrepancies in reports regarding changes in
synaptic proteins in AD brain tissue,14,15,25
we undertook
systematic measurements of four distinct synaptic proteins:
synaptophysin, syntaxin, SNAP-25, and -synuclein. The first three
showed an essentially identical biphasic profile with respect to
neuropathological stage (Figure 4)
.
Synaptophysin, syntaxin, and SNAP-25 were significantly increased at
stage 3 (Table 2)
, and these levels decreased at more advanced
neuropathological stages. Only the decrease in the syntaxin level
relative to stage 3 reached statistical significance (Table 2)
. By
contrast, the profile for -synuclein was essentially identical to
that of MAP2 (see below).
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-Synuclein
We examined levels of MAP2 protein as a marker for change in the
dendritic cytoskeleton. In contrast to PHF-tau and phosphorylated tau
protein, MAP2 protein underwent a biphasic course similar to that seen
for synaptic proteins. In this case, however, a statistically
significant increase was not detected until stage 4, with significant
declines observed in stages 5 and 6 (Figure 5
; Table 2
). Interestingly, levels of
-synuclein followed an almost identical course, with a transient and
statistically significant increase at stage 4 (Figure 5
; Table 2
).
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We undertook an analysis of the data with respect to clinical stage, as measured at the last clinical assessment before death, to relate neurobiological changes to clinical progression. CAMDEX provides five clinical stages: normal, minimal, mild, moderate, and severe.13 The normal and minimal stages do not meet DSM-III-R criteria for clinical dementia. For the purpose of this analysis, seven cases with vascular dementia were excluded.17,18 The overall pattern, described briefly below, was essentially identical to that derived from the neuropathological staging.
Neuropathology
No -immunoreactive pathology was detected in the neocortex in
cases coming to postmortem without clinical evidence of dementia before
death, although appreciable numbers of ß-amyloid plaques were
detected in these cases. These normal cases were significantly distinct
from those with a minimal level of dementia before death in terms of
tangles, neuritic plaques, and ß-amyloid plaques (Figure 6
; Table 3
). More advanced clinical stages of
dementia were associated with further step-wise increases in
neocortical tau pathology, although the next significant increase in
ß-amyloid plaques was not detected until dementia had reached the
severe stage. Clinical severity was therefore more strongly correlated
with tau pathology (0.50 < < 0.55; P <
0.0001) than with ß-amyloid plaques ( = 0.30).
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Significant levels of both PHF-tau and phosphorylated tau were
detected in cases without any clinical evidence of dementia (Figures 7 and 8)
.
Cases with minimal dementia had significantly higher levels of PHF-tau
than those with normal mental function before death (Figure 7
and Table 3
). There were further increases in PHF-tau for each further grade of
severity of dementia (Table 3
; 0.36 < < 0.43). By
contrast, phosphorylated tau in non-PHF fractions first increased
significantly over the nondemented background level only when dementia
had progressed to the mild stage (Table 3)
.
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The observation that the levels of synaptic proteins in
neocortex increase significantly over the normal aged background at
intermediate stages of AD was confirmed in the clinical analysis. Cases
with a mild degree of dementia had significantly higher levels of
synatophysin and SNAP-25 in neocortex than cases with no dementia or
minimal dementia (Figure 9
and Table 3
).
It was only when dementia had reached the moderate stage that the
levels of synaptophysin, syntaxin, and SNAP-25 began to show
significant decline (Table 3)
. Exclusion of the normal and minimal
cases maximized the correlations between levels of synaptic proteins
and clinical severity (0.31 < < 0.41).
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There was no counterpart in the analysis undertaken with respect to clinical stage for the significant Braak stage 4 changes detected in these proteins.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Staging based on the pattern of pathology in medial temporal and limbic structures correctly predicts the accumulation of PHF-tau in the isocortex before histological evidence of neurofibrillary degeneration. Whereas neurofibrillary tangles and neuritic plaques do not begin to appear until stage 4 in the isocortex, PHF-tau can be detected at significant levels from stage 2 onwards, and increases in a step-wise manner with respect to stage thereafter. Accumulation of PHF-tau in the isocortex likewise distinguishes nondemented cases from those with a minimal degree of dementia before death, and increases in a step-wise manner with respect to clinical stage. The PHF-tau we have detected at stage 2 and thereafter is characterized by: having the sedimentation properties characteristic of 88% of PHFs in the brain;10 containing acid-reversible aggregates through the repeat domain,4 forming proteolytically stable complexes truncated at Glu-391,36 and being associated with full-length tau phosphorylated at Ser-199/202.10 These sedimentation and immunochemical features provide a basis for defining the species first accumulating at stage 2 as PHF-tau.
These changes in PHF-tau can be contrasted with other forms of phosphorylated tau which do not sediment with PHFs. Sarkosyl-insoluble tau appears only by Braak stage 4, and soluble hyperphosphorylated tau by stage 6. In terms of clinical severity, phosphorylated tau increases over the normal aging background at the level of mild dementia, whereas PHF-tau increases at the level of minimal dementia. Therefore forms of phosphorylated tau not sedimenting with the bulk PHF fraction appear after the onset of tau aggregation forming PHFs. It has been proposed that phosphorylation of tau causes early pooling as a result of microtubule detachment and later aggregation to form PHFs.29-34 Our findings are inconsistent with this hypothesis: tau aggregation precedes the pooling of soluble hyperphosphorylated tau. Similarly, MAP2 protein changes occur later than tau aggregation: increased levels lag by two Braak stages and decline by four stages. It seems unlikely that a common mechanism such as disruption of the normal regulatory balance of kinases and phosphatases could be considered responsible both for the aggregation of tau protein, pooling of soluble phosphorylated tau, and the later changes in MAP2, as they occur at widely divergent stages of the disease process.
In contrast to the progressive accumulation of aggregated tau protein,
the changes seen in four distinct synaptic proteins and MAP2 are
biphasic with respect to both pathological and clinical staging. Braak
stage 3 is characterized in the neocortex by increased levels of
synaptophysin, syntaxin, and SNAP-25. Increases in MAP2 and
-synuclein do not arise until Braak stage 4. Iwai et
al37
also described slightly increased levels of
immunoreactivity for synuclein in the frontal lobe at early AD stages.
The subsequent decrease in presynaptic proteins, synuclein, and MAP2
was seen only after the appearance of the full spectrum of
tau and ß-amyloid pathology. Conversely, the presence of ß-amyloid
pathology in the absence of tau pathology was not associated with any
loss of synaptic proteins. Therefore, our results, like those of
Masliah et al38
and Terry et al15
, are
inconsistent with the hypothesis that synapse loss in isocortex is due
solely to advanced stages of ß-amyloid plaque
deposition.27,28
The increase in ß-amyloid plaques
associated with progression of AD first becomes evident at stage 4,
after the onset of PHF-deposition at stage 2, and the transient
increase in synaptic proteins at stage 3. This sequence observed in
human isocortex is the reverse of that expected according to the
hypothesis that extracellular ß-amyloid deposits initiate the
cytoskeletal and synaptic changes of AD.27,28
This is
further supported by the findings of a recent study, which described
accumulation of longer amyloid isoforms (Aß42)
in the human brain to appear rather early (from the fourth decade
onwards), but is a variable feature in the brain tissue of
octogenarians and nonagenarians.39
Immunohistochemical studies have suggested that there is extensive synapse loss during aging, with estimates varying between 20 to 25% comparing younger individuals with those aged 60 or more, with some degree of overlap with the losses found in AD.40-45 In the present study we confirm that advanced stages of AD are associated with a further loss of synaptic vesicle proteins in excess of that associated with normal aging. This is consistent with studies showing loss of synaptophysin in tangle-bearing neurons,46 and a high correlation between tangle counts and neuronal loss.47 The mini mental state exam (MMSE) score of 20 used as an exclusion criterion by Terry et al15 implies that only cases with mild or greater severity of dementia were included in the latter study. When this exclusion criterion was applied to the present cases, the correlation between loss of synaptic protein and clinical severity could be reproduced. However, this does not imply that loss of synapses is the neurobiological substrate of early dementia. Minimal dementia was observed in the absence of synaptic loss, and mild dementia was associated with significantly higher levels of synaptophysin and SNAP-25. Therefore, loss of synapses in association neocortex cannot provide a simple explanation for the early stages of dementia.
The mechanism responsible for the transient increase in synaptic
protein levels in association neocortex at stage 3 is at present
unknown. Neuritic sprouting has been described in AD, associated
predominantly with -immunoreactive neuritic plaques.48
Furthermore, the extent of tau phosphorylation has been associated
particularly with dendritic sprouting.49
However, we did
not detect any increase in -immunoreactive neuritic plaques or
neuropil threads until Braak stage 4. Likewise, ß-amyloid plaques and
neurofibrillary tangles also increased only from stage 4, as were
changes in phosphorylated tau protein in the soluble and
sarkosyl-insoluble fractions. Therefore, the increase in synaptic
protein levels precedes any of the changes that have been linked with
neuritic sprouting.
Numerous trophic factors have been identified which mediate neuronal sprouting responses to neuronal injury and partial de-afferentation.50-52 Recent experimental studies found that synaptic loss and dendritic atrophy after ischemic lesions could be ameliorated by infusion of human nerve growth factor (NGF),52-54 and increased levels of NGF have been found in AD brain.55,56 Thrombin, which induces cell spreading, has also been found to increase Alz-50 immunoreactivity.57 Many growth-promoting factors have been localized to the corona of neuritic plaques, including GAP-43,58 collagen IV, laminin and the integrin receptor VLA6,59 transforming growth factor-ß,60 and fibroblast growth factor.61 Interestingly, growth factors have been identified in the corona of plaques before the appearance of phosphorylated tau protein,59 consistent with our finding that synaptic proteins increase before the accumulation of phosphorylated tau protein in the soluble and sarkosyl-insoluble fractions.
Little is known about MAP2 protein metabolism in aging and in AD. Although initial studies suggested that tangles contain MAP2 immunoreactivity,62 MAP2 sequences were not identified either in the PHF core63 or in other PHF preparations.64 Most neuritic plaques do not contain any MAP2 immunoreactivity, and MAP2 immunoreactivity decreases at advanced stages of AD, particularly in entorhinal cortex (E. B. Mukaetova-Ladinska, unpublished observations). Increased expression of MAP2, particularly MAP2c, has been associated previously with neuronal trophic responses in a variety of settings.65-68 Whatever the mechanism of induction of increased levels of MAP2 protein at stage 4, our findings are consistent with histological evidence for transient dendritic sprouting in the CA 1 region of the hippocampus at early stages of AD.69 The fact that MAP2 and synuclein levels increase one stage after the presynaptic proteins argues against a single common mechanism, such as nonspecific reduction in turnover or transportation.
A more complex picture of synaptic pathophysiology seems to be emerging. The loss of synaptic proteins is a relatively late phenomenon in the isocortex, occurring well after the onset of clinically detectable dementia, and also after the appearance of the full spectrum of classical plaque and tangle pathology. The earliest detectable change relative to the normal aging background is the onset of tau protein aggregation at stage 2, which is consistent with our earlier immunohistochemical70 and biochemical11 staging studies in medial temporal lobe structures. We have recently reported that proteolytically stable truncated tau aggregates, once formed, have the capacity to propagate further tau capture via a high-affinity binding interaction.35 The present data and our earlier evidence showing exponential redistribution of the tau protein pool in AD7,11 would be consistent with a sequence of aggregation events which would divert tau protein away from microtubules and account for the failure of axonal transport. Our results are consistent with the hypothesis that early accumulation of PHF-tau is associated with impairment of axonal transport that elicits an early adaptive synaptic regeneration response. This transient response cannot be sustained, but is followed by loss of synaptic proteins at more advanced stages. An impairment of axonal transport associated with PHF accumulation may therefore make an important contribution to early dementia. Our results suggest whatever the upstream factors which are ultimately responsible for the onset of tau aggregation, a therapy targeting this process35 would provide a means of intervening early in a cascade which is closely linked to the onset and progression of clinically detectable dementia.
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Acknowledgements |
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Footnotes |
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Supported by MRC Grant United Kingdom (to E. B. M.-L., J. H., J. H. X., C. R. H., C. M. W.), MRC Grant, Canada (to W. H.), CONACyT Mexico, and the Alzheimer’s Research Fund, Cambridge (F. G.-S.).
E. B. M.-L. is a Research Fellow of Hughes Hall, University of Cambridge.
Accepted for publication May 9, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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