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Regular Articles |
From the Center for Neurologic Diseases,*
Brigham and
Women’s Hospital and Harvard Medical School, Boston, Massachusetts;
Harvard College,
Cambridge, Massachusetts; New
York State Institute for Basic Research and Developmental
Disabilities,
Staten Island, New York; and
the Department of Neurology,§
New York
University, New York, New York
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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30 years) DS brain to show extensive complement IR was that of a
29-year-old DS subject who also displayed the full range of AD
neuropathological features. All middle-aged and old DS brains showed IR
for Clq and C3, primarily in compacted plaques. In these
cases, C4d IR was found in a subset of Aß42 plaques
and, along with C5b-9 IR, was localized to dystrophic
neurites in a subset of neuritic plaques, neurons, and
some NFTs. Our data suggest that in AD and DS, the classical
complement cascade is activated after compaction of Aß42 deposits
and, in some instances, can progress to the local
neuronal expression of the MAC as a response to Aß plaque
maturation.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In AD brains, compacted Aß plaques are often associated with such inflammatory markers as activated microglia, reactive astrocytes, and complement proteins, including Clq, C3, C9, C3d, and C4d.12-15 The complement cascade comprises a series of enzymatic steps that play a role in the immune response.16 Clq, C3, and C9 are three proteins involved in the beginning, middle, and end, respectively, of the classical complement cascade. Whereas the classical complement pathway is more commonly activated by the binding of Clq to the Fc portion of an immunoglobulin, aggregated Aß but not monomeric Aß17 has been reported to activate the classical complement cascade by directly binding to Clq in vitro.18-24 Synthetic preaggregated Aß42 peptides were observed to bind Clq much more effectively than Aß40 peptides, and the binding site of the Aß42 peptides was localized to the Clq A chain collagen-like region, residues 14–26.19 Binding of Aß to Clq has been shown to enhance Aß aggregation because of the complementary spacing in the structures of the two proteins.20 Moreover, in situ evidence for the activation of the classical complement pathway has been observed in AD brain.15,18,25-27 This cascade marks cells for attack by macrophages and causes the release of various proteins to serve as anaphylotoxins that further stimulate the immune response. The cascade ends in the assembly of two molecules of preassembled C5b, 6, 7 with two molecules of C8 and subsequently 12–18 molecules of C9 to form the membrane attack complex (MAC), C5b-9, which creates a leaky pore in the plasma membrane and leads to lysis of target cells.28 C4d and C3d constitute by-products of degradation of C4b and C3b on the cell surface and indicate complement activation; immunoreactivity (IR) for each has been observed in senile plaques, dystrophic neurites, and NFTs in AD.28 The presence of C4d is indicative of activation of the classical pathway, whereas C3d is indicative of either the classical or alternative complement pathways.29 C5b-9 IR has been detected in dystrophic neurites in senile plaques (but not in association with extracellular amyloid) and in NFTs in AD.26,28 Apo-J, an inhibitor of the membrane attack complex, has been shown to colocalize with senile plaques in AD and DS cerebral cortex.30 Furthermore, apo J has been observed to complex with soluble Aß in cerebrospinal fluid.31 The activation of the alternative complement pathway by Aß peptides has also been described.32
The purpose of the current study was to characterize the temporal appearance of several complement proteins (Clq, C3, C4d, and C5b-9) as well as the complement inhibitor, apo J, in DS brain and to relate this process to other AD neuropathological changes: Aß42 deposits, dystrophic neurites, reactive astrocytes, and activated microglia. Thus the activation, progression, and completion of the classical complement cascade were examined in a temporal series of DS brains of increasing ages and compared to the classical changes of AD.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Autopsied brains from 24 DS patients were examined. These brains are part of a collection of DS tissue obtained by us over the past 13 years. The cases were divided into young (12–30 years), middle aged (31–50 years), and old (51–73 years) for the purpose of temporal comparison. Tissues from the young cases were kindly provided by Dr. Krystyna Wisniewski (Institute for Basic Research in Developmental Disabilities, Staten Island, NY).
Tissue Preparation
Blocks of DS frontal cortex were briefly fixed (1–48 hours) or
routinely fixed (more than 48 hours up to 1 year) in 10% neutral
buffered formalin. These fixation times are respectively designated
"short" and "long" in Table 2
. Young cases were fixed "very
long," ie, a period of formalin fixation exceeding 1 year. The exact
formalin fixation times of the young cases are unknown but exceed 1
year and, in some instances, may exceed 10 or more years. After
fixation, the brain tissue was dehydrated and embedded in paraffin.
Eight-micron serial sections were cut, dried, and baked at 60°C for 1
hour.
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The antibodies listed in Table 1
were used to immunostain the DS brain sections. Tests were performed on
briefly, routinely, and long-term-fixed, paraffin-embedded AD tissue to
determine the best staining conditions for each antibody. 21F12 (gift
of Elan Pharmaceuticals, San Francisco, CA) is a mouse monoclonal
antibody that selectively recognizes Aß peptides ending at residue 42
and was used to detect diffuse and compacted Aß
plaques.33
A monoclonal antibody directed against paired
helical filament (PHF) tau protein, AT8 (Innogenetics, Belgium), was
used to detect NFTs, neuropil threads, and plaque-associated dystrophic
neurites. A monoclonal antibody directed against phosphorylated
neurofilament protein, SMI-34 (Sternberger Monoclonals, Baltimore, MD),
was also used to detect NFTs and dystrophic neurites. Rabbit anti-human
glial fibrillary acidic protein (GFAP) (Dako, Carpinteria, CA) was used
to label reactive astrocytes. Rabbit anti-human ferritin (Sigma
Chemical Company, St. Louis, MO) was used to detect microglia
associated with Aß plaques in all DS cases. Mouse anti-human HLA-DR
(Neomarkers Corp., Fremont, CA) was used to detect activated microglia
in middle-aged and older DS cases but was nonreactive in the very
long-term-fixed young DS cases. Rabbit anti-human Clq (Dako) was used
to detect Clq. Goat anti-human C3 (Quidel Corp., San Diego, CA) was
used to label C3. Mouse anti-human C4d (Quidel Corp.) was used to label
C4d. Mouse anti-human SC5b-9 (Quidel Corp.), directed at a neoepitope
on C9 that is present only when the membrane attack complex has been
assembled, was used to detect C5b-9.34
Goat anti-human apo
J (Rockland, Gilbertsville, PA) was used to detect apo J in single- and
double-labeling experiments. Cell nuclei were counterstained with
hematoxylin.
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Single Primary Antibody Labeling Experiments
Sections were deparaffinized in Histoclear (National Diagnostics,
Atlanta, GA) and rehydrated. Endogenous peroxidase activity was
quenched by incubation of the sections in 0.3% hydrogen peroxide in
methanol for 5 minutes. The sections were washed in water for 5
minutes. Appropriate pretreatments were carried out for each primary
antibody as designated in Table 1
. Formic acid pretreatment consisted
of the application of 88% formic acid to sections for 15 minutes,
followed by a 5-minute water wash. Microwave pretreatment consisted of
heating sections in a citrate buffer (BioGenex, San Ramon, CA) until
the solution came to a boil. The heat level was then reduced to provide
gentle cyclic boiling for an additional 5 minutes. Sections were cooled
to room temperature and washed in water. Proteinase K pretreatment
entailed applying a 1:100 dilution of proteinase K (Dako) in 50 mmol/L
Tris buffer (50 mmol/L Tris-HCl, pH 7.6) onto sections for 8 minutes.
Sections were then rinsed in water briefly and washed in Tris-buffered
saline (TBS) for 5 minutes. After these various pretreatments, all
sections were blocked for 20 minutes in 10% goat serum (for GFAP and
ferritin), 10% horse serum (for 21F12, AT8, SMI-34, and HLA-DR), or
3% bovine serum albumin (BSA) (for apo J, Clq, C3, C4d, and C5b-9).
Sections were incubated with primary antibody overnight at 4°C. The
horseradish peroxidase avidin-biotin complex system (rabbit, mouse, or
goat Elite ABC kits; Vector Laboratories, Burlingame, CA) and
diaminobenzidine (DAB) (Sigma Immunochemicals, St. Louis, MO) were used
to visualize the bound antibodies. To minimize variability in staining
intensity for each antibody used, sections from all of the DS cases
were immunostained simultaneously. Sections were counterstained with
hematoxylin, differentiated with acid alcohol, dehydrated, cleared in
Histoclear, and coverslipped with Permount (Fisher Scientific,
Pittsburgh, PA).
Double Primary Antibody Labeling Experiments
In a few DS cases of varying age, double-label immunostaining was carried out to assess colocalization between selected proteins more directly. To detect two primary antibodies on one section, the procedure described in the previous section was followed for the first antibody. After DAB development, the sections were rinsed in water for 5 minutes. Any necessary pretreatments for the second antibody were carried out, and the sections were rinsed in water for 5 minutes. After blocking with 3% BSA for 20 minutes, the sections were incubated in the second primary antibody overnight at 4°C. After a 30-minute incubation with the corresponding secondary antibody, the alkaline phosphatase kit (AP ABC kit; Vector Laboratories) was used with a red substrate (Alkaline Substrate Kit 1; Vector Laboratories) to visualize the second primary antibody. Sections were counterstained in hematoxylin, differentiated with acid alcohol, dehydrated, and coverslipped with Permount.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our 24 DS cases were divided into young (12–30 years), middle
aged (31–50 years), and old (51–73 years) for the purpose of temporal
comparison (Table 2
and Figure 1
). Diffuse Aß42 plaques were first
observed in the 12-year-old DS brain (not shown but illustrated in Ref. 8
). GFAP-reactive astrocytes associated with Aß42 plaques and some
dystrophic neurites were first labeled in the 15-year-old DS case (not
shown). This 15-year-old patient had exceptionally compacted Aß42
plaques, whereas the other teenage DS cases had overwhelmingly diffuse
(noncompacted) Aß42 plaques; the number of compacted amyloid plaques
in these young cases was judged in part from previous thioflavin S
staining experiments (not shown). The presence of tau-positive
dystrophic neurites in compacted Aß42 plaques was first observed in
the 15-year-old DS brain, whereas NFTs were first observed in the
29-year-old case. None of the other young cases had neuritic plaques or
NFTs (Table 2)
.
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and Table 2
). The 16-, 17-, and 27-year-old cases
showed a very small number of reactive astrocytes. The amount of
GFAP-positive astrocytes associated with blood vessels was greater in
the 12-year-old subject with Aß42 plaques than in the 23-year-old
subject, who did not show any Aß42 plaques. Plaque-associated
reactive astrocytes were readily observed in all middle-aged and old DS
subjects (Figure 1, k and q
, and Table 2
).
A ferritin antibody was used to label microglia in all of the DS cases,
because the long fixation precluded using the HLA-DR antibody in the
young cases. Ferritin-positive microglia, associated with a small
subset of compacted Aß42 plaque deposits, were first observed in the
brain of the 15-year-old DS subject. Plaque-associated
ferritin-positive microglia were more frequently observed in the
29-year-old DS subject (Figure 1c)
. None of the other young cases
showed plaque-associated ferritin microglia (Table 2)
, but all young
cases had ferritin-positive microglia near blood vessels and in white
matter. Activated microglia, frequently associated with Aß42 plaques,
were labeled by both the ferritin and HLA-DR antibodies in all
middle-aged and old DS brains (Figure 1, i and o)
. As with ferritin at
all ages, HLA-DR-positive microglia were also intensely labeled in
white matter and blood vessels in many middle-aged and old DS subjects.
Furthermore, HLA-DR- and ferritin-positive microglia were observed to
have varying morphologies in gray matter. The more lightly labeled
microglia tended to have longer processes and small cell bodies (ie,
resting microglia), whereas the more intensely labeled microglia had
shorter processes and larger cell bodies (ie, activated microglia;
Figure 1i
). Microglia in the latter form were more often associated
with Aß42 plaques than were other labeled microglia.
Temporal Deposition of Complement Protein in DS Brains
Clq and C3 Immunoreactivities
Clq IR in plaques was first detected in the 15-year-old DS brain
and was closely associated with compacted Aß42 staining (Table 2)
.
Clq-labeled deposits were not seen in the brain of the
12-year-old DS patient, our youngest, who had overwhelmingly diffuse
Aß42 plaques. Weak Clq IR was detected in a small subset of
semicompacted Aß42 plaques in the 16-year-old patient. The
29-year-old patient was the only other young subject to show Clq IR
deposits (Figure 1b)
; these deposits colocalized strongly with reactive
astrocytes but only moderately with microglia, C3, and dystrophic
neurites (Figure 1, b–f)
. The 15-year-old and 29-year-old DS patients
showed more compacted Aß42-IR plaques, some with activated glia
and/or degenerating neurites, than the other young patients.
All middle-aged and old DS patients showed Clq deposits strongly
associated with the large majority of compacted Aß42 plaque deposits
(Figure 1, g and h
, and Figure 1, m and n
). These patients showed more
Clq IR than the two young patients (aged 15 and 29 years), reflective
of the increase in compacted, mature plaques in the older cases. Clq IR
colocalized closely with Aß42 plaques in all cortical layers,
although some diffuse subpial and white matter Aß42 deposits appeared
to lack Clq IR. Overall, Clq IR was associated with the largest number
of Aß42 plaques when compared to the immunoreactivities of the other
complement proteins.
In serial sections, Clq IR frequently overlapped with C3 IR, activated
microglia, reactive astrocytes, and plaque-associated dystrophic
neurites in middle-aged and old DS patients (Figure 1, h–l
, and Figure 1, n–r
). The colocalization of Clq with activated microglia and
dystrophic neurites in plaques was confirmed by double-labeling
sections from a subset of patients from each age group; results for the
29-year-old and the 73-year-old DS patients are illustrated in Figure 2
. Clq IR was found in many plaques
containing activated microglia in their centers (Figure 2, a and e)
. In
addition, Clq IR overlapped with neuritic plaques in these two patients
(Figure 2, b and f)
.
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and was closely associated with compacted Aß42 IR plaques.
Weak C3 IR was observed in a minority of Aß42 plaques in the
16-year-old patient. In the 29-year-old patient, C3 IR was seen in the
centers of a subset of Aß42 plaques and colocalized to some degree
with Clq, microglia, reactive astrocytes, and a few dystrophic neurites
(Figure 1, a–f)
. None of the remaining young patients showed C3 plaque
staining. Middle-aged and old DS cases showed C3 IR in Aß42 plaques,
in association with Clq, activated microglia, reactive astrocytes, and
dystrophic neurites (Figure 1, g–l
, and Figure 1, m–r
). C3 IR was
observed in a smaller subset of Aß42 plaques than was Clq IR. C3 IR
was absent from most of the subpial and deep cortical Aß42 deposits
found mainly in old DS cases. Double-labeling experiments in a subset
of patients from each age group confirmed the colocalization of C3 with
activated microglia and neuritic plaques, as shown in Figure 2
for the
29-year-old (c and d) and the 73-year-old (g and h) patients. C4d and C5b-9 IR
C4d IR was first detected in a small number of compacted plaques
and focally in scattered groups of neurons in the 15-year-old DS
patient (Table 2)
. Weak neuronal C4d IR was also observed in the
16-year-old and 17-year-old patients. A few compacted plaques,
dystrophic neurites, and NFTs, in addition to abundant neuronal
staining, were detected using the C4d monoclonal in the 29-year-old
patient (Figure 3d)
. C4d IR in amyloid
deposits and plaque-associated dystrophic neurites was observed in
roughly half of the middle-aged and old DS cases; however, focal
neuronal and some NFT staining was detected in most of these cases
(Figure 3i
and Table 2
). C4d plaque staining overlapped with Aß42 and
was frequently accompanied by the presence of microglia and dystrophic
neurites (Figure 3
, a–d, f–i). After we doubly pretreated the
long-term and very long-term-fixed tissues with microwave heating
followed by formic acid, focal neurons and/or NFTs were detected using
the C5b-9 antibody in those brains bearing consolidated Aß plaques,
including that of the 15-year-old and the 29-year-old (Table 2
and
Figure 3, e and j
) patients. General, low-level neuronal C5b-9 IR was
observed in most DS brains, regardless of age; however, with the
appearance of compacted plaques, dystrophic neurites, NFTs, and
gliosis, a more intense focal labeling of C5b-9 in neurons was
detected. As with C4d, the presence of multiple markers of AD
pathology, including Aß, ferritin, and tau, was observed in the same
vicinity as the C5b-9 IR in adjacent sections (Figure 3)
. C5b-9-IR
dystrophic neurites were observed in plaques in five of six available
briefly fixed brain tissues and in two long-term-fixed middle-aged and
old DS brain tissues (Table 2)
.
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Apo J IR was first observed within compacted Aß42 plaques in the
15-year-old DS patient (Table 2)
. Apo J-IR deposits were observed in
three young patients (15, 27, and 29 years); all three of these cases
had moderate to numerous compacted Aß42 plaques. Apo J IR was
observed in all middle-aged and old DS subjects. In general, the
relative abundance of apo J IR most closely resembled that of Clq IR.
Apo J IR colocalized with Aß42-IR plaques in all cortical layers.
Double-labeling experiments demonstrated the colocalization of apo J
with Aß42 plaques and plaque-associated reactive astrocytes in brains
of the 15-, 46-, and 65-year-old DS patients (Figure 4, a, c, and e)
. Reactive astrocytes were
often observed surrounding the apo J-IR deposits, with their processes
extending into these deposits (Figure 4, b, d, and f)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of this study suggest that the presence of complement IR in plaques is dependent on the state of compaction and maturation of Aß42-IR plaques; those brains with more compacted Aß plaques, dystrophic neurites, and plaque-associated gliosis showed more complement IR. Thus, the more severe the AD pathology, regardless of age, the greater the inflammatory response. Several observations support this conclusion. First, abundant Clq and C3 deposits were detected in only two of the young DS cases (15 and 29 years). These two patients showed more severe AD neuropathology, such as compacted plaques, reactive astrocytes, activated microglia, and neuritic changes, than did the other young DS patients (which had predominantly diffuse plaques), and the two patients appear to represent an accelerated form of the AD process in DS. All middle-aged and old DS patients had many compacted Aß42 plaques and abundant Clq and C3 plaque IR. Second, diffuse white matter Aß42 plaques observed in several old DS patients did not have associated complement Clq IR, despite the presence of strong Clq staining in other, more compacted plaques in both gray and white matter in the same section. In addition, diffuse subpial deposits of Aß42 were most prevalent in old DS patients and were not Clq immunoreactive. The absence of Clq subpial staining in tissue that was otherwise clearly labeled by the Clq antibody supports the result obtained in young DS brains, in which complement staining was not observed in those cases bearing only diffuse Aß42 plaques. These results are in agreement with previous work by Afagh et al, in which the authors describe an absence of Clq IR in thioflavin-negative diffuse plaques in the brains of AD patients and nondemented controls.15 In addition to plaque labeling by Clq antibodies, others have reported the staining of dystrophic neurites and some NFTs, using other Clq antibodies.28 We were unable to detect Clq labeling of such structures; however, fixation techniques and the use of a different antibody may account for the reduced sensitivity we observed.
Compared to Clq-labeled plaques in the 15- and 29-year-old and older patients, fewer plaques were IR for C3. Lower sensitivity of the antibody on long-fixed paraffin sections may be a reason for this diminution in C3 staining relative to that of Clq. A strong association between C3 IR in plaques and activated microglia was observed in the two young cases and in all middle-aged and old DS cases. Activated microglia (with shortened, thickened processes and large cell bodies) were often associated with Aß plaques and stained more intensely than resting microglia with antibodies to HLA-DR and ferritin. Previous work by Walker et al showed that cultured microglia from postmortem human brain express complement proteins, suggesting microglia as a potential source for these proteins.35
C4d and C5b-9 immunoreactive dystrophic neurites and NFTs, indicators of classical complement activation, were detected in the aforementioned two young patients (aged 15 and 29 years) and in most of the middle-aged and old DS cases. C4d IR was also observed in a subset of senile plaques in many of these cases. In many cases of all ages, both C4d and C5b-9 antibodies demonstrated broadly distributed, weak neuronal staining, primarily of pyramidal neurons, even in the absence of glial activation or visible neurodegenerative changes. In those cases having more severe AD pathology, focal groups of neurons, in addition to nearby dystrophic neurites and NFTs, were stained much more intensely, and this may indicate some intermediate stage of cell lysis and neurodegeneration. Previously, Terai et al36 showed that pyramidal neurons in AD brain express the complement proteins involved in the classical pathway. However, because C4d is a by-product of degradation that signals complement activation and C5b-9 is assembled from several complement proteins, it seems unlikely that the neuronal staining we observed is due to actual localization of C4d and C5b-9 with each of the weakly labeled neurons. Instead, doubly pretreating the strongly fixed sections with microwave heating and formic acid may have allowed some cross-reactivity of the antibodies with other complement proteins or with other neuronal proteins. The intense labeling of C4d and C5b-9 in a subset of dystrophic neurites associated with senile plaques and in NFTs suggests that the classical complement pathway was activated and progressed to completion in those structures. However, the levels of "specific" C4d and C5b-9 staining were low relative to that of Clq and C3, thus indicating that the initiation of the complement cascade by the binding of Clq to Aß does not necessarily progress to the MAC. This conclusion is in agreement with previous in vitro studies by Cadman et al,37 in which the authors found that high levels of Aß peptides, able to activate early complement cascade components, showed lower levels of MAC formation than expected.
Overall, our data suggest that complement proteins are abundant in compacted Aß plaques. Aß can directly activate the complement cascade via binding to Clq in in vitro experiments.18-24 The prevalence of Clq in Aß plaques suggests that the complement cascade is available for activation. The observation of abundant C3 IR in Aß plaques suggests that the components necessary for progression of the cascade are available and in the right location. C4d and C5b-9 IRs in the brains of two young and all middle-aged and old DS patients suggest that the complement cascade is activated and can progress to completion. Moreover, the large number of activated microglia, reactive astrocytes, and dystrophic neurites, as markers of inflammation and potential sources of complement proteins, suggests that the cascade is active in the AD-type lesions that occur in DS.
Apo J, a known inhibitor of C5b-9, showed much more IR than either C4d or C5b-9. This result is supportive of the role of apo J in inhibiting the complement cascade end product, C5b-9 (membrane attack complex; MAC), and provides indirect evidence of complement activation in AD. Apo J IR colocalized with many Aß plaques. In addition to inhibiting MAC formation, it may perform other functions. As a minor species of high-density lipoproteins, it is thought to carry out lipid transport functions.38 Its secretion from reactive astrocytes may be an early immune response, as apo J has been observed to slow the aggregation of Aß in vitro.39,40
Our results suggest that AD and DS brains provide a primed environment for complement-mediated inflammation. The potential negative effects of an active complement cascade in the brain are several. First, Clq has been shown to enhance Aß aggregation and promote nucleation.20 Such events would be predicted to accelerate plaque maturation, including associated inflammatory responses, and to reduce the likelihood of clearance of Aß. Second, the vast proliferation of C3 molecules could mark healthy neighboring cells near the plaque for phagocytosis. Third, if the C5b-7 complex, the precursor form of the MAC that attaches to available cell membranes, is not near a target cell, it will engage in the cell membrane of a neighboring cell, causing cell lysis. This process is called bystander lysis.16,41 The complement cascade is thought to be activated because of Aß plaque deposition but presumably is not capable of eliminating the extracellular amyloid deposits, which lack cellular membranes and other features that are required for cell lysis by MAC. However, C5b-9 IR has been observed in dystrophic neurites within Aß plaques, a more reasonable target of complement-mediated cell lysis.23,26,42 Furthermore, the complement cascade can excite the respiratory burst apparatus in microglia43,44 which can then activate them to create free radicals. This highly oxidative environment appears to be conducive to neuronal degeneration. Thus therapeutic interventions aimed at slowing or halting this cascade of inflammation in response to compacted Aß in the brain may be of value in treating or preventing AD.
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Footnotes |
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Supported by National Institutes of Health grants AG06173 and AG15408.
Accepted for publication October 26, 1999.
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