T lymphocytes potentiate endogenous
neuroprotective inflammation in a mouse
model of ALS
Isaac M. Chiua,1, Adam Chenb, Yi Zhenga, Bela Kosarasc, Stefanos A. Tsiftsogloua, Timothy K. Vartanianc,
Robert H. Brown Jr.b, and Michael C. Carrolla
aDepartment of Pathology, Immune Disease Institute, andcBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; andbDay
Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, MA 02129
Edited by Jack L. Strominger, Harvard University, Cambridge, MA, and approved September 18, 2008 (received for review May 13, 2008)
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive,
motor neuron degenerative disease, in which the role of inflam-
mation is not well established. Innate and adaptive immunity were
investigated in the CNS of the Superoxide Dismutase 1 (SOD1)G93A
transgenic mouse model of ALS. CD4?and CD8? T cells infiltrated
SOD1G93Aspinal cords during disease progression. Cell-specific
flow cytometry and gene expression profiling showed significant
phenotypic changes in microglia, including dendritic cell receptor
acquisition, and expression of genes linked to neuroprotection,
cholesterol metabolism and tissue remodeling. Microglia dramat-
ically up-regulated IGF-1 and down-regulated IL-6 expression.
When mutant SOD1 mice were bred onto a TCR? deficient back-
ground, disease progression was significantly accelerated at the
symptomatic stage. In addition, microglia reactivity and IGF-1
levels were reduced in spinal cords of SOD1G93A(TCR??/?) mice.
These results indicate that T cells play an endogenous neuropro-
tective role in ALS by modulating a beneficial inflammatory re-
sponse to neuronal injury.
amyotrophic lateral sclerosis ? microglia ? neuroimmunology ?
neuroinflammation ? T cells
inherited form of Amyotrophic Lateral Sclerosis (ALS) is linked
to mutations in the Cu2?/Zn2?superoxide dismutase (SOD1)
gene (1). Mice overexpressing human mutant SOD1 develop
motor pathology resembling ALS (2).
In human patients and mutant SOD1 transgenic mice, loss of
motor neurons is accompanied by robust microglia and astrocyte
activation (3). Several lines of evidence implicate involvement of
non-neuronal cells in ALS. Blastocyst chimera studies showed
that mutant SOD1 expressed by neighboring cells negatively
affected survival of motor neurons (4). Conditional deletion
experiments demonstrated that mutant SOD1 reduction in
CD11b? myeloid cells, including microglia, lengthened lifespan
(5). Neonatal bone marrow transplants, replacing the microglia
niche with wild-type cells, also ameliorated disease in mice (6).
One mechanism for microglia induced neurotoxicity may be
reactive oxygen species through NADPH oxidase (7). The role
of inflammation in neurodegenerative disease, however, is com-
plex and may effectuate both beneficial and harmful outcomes
on neuronal survival (8).
Activation of innate (e.g., microglia) and adaptive (e.g., T
cells) immunity has been documented in mutant SOD1 mice (9,
10). Prior studies on neuroinflammatory changes resulted from
whole spinal cord expression profiling (11, 12). Mutant SOD1,
however, dysregulates multiple cell types—including astrocytes
(13, 14), motor neurons, and microglia (5). Therefore, a targeted
analysis of immune cell types is necessary to define their
particular roles in ALS.
In this study, we characterized microglia and lymphocytes
directly isolated from the CNS of SOD1G93Atransgenic mice,
LS is characterized by selective degeneration of motor
neurons, leading to paralysis and death. The most common,
and analysis of these cells identified significant changes in
surface receptor profiles and neurotrophic factor expression.
Specific ablation of T cells led to decreased microglia reactivity,
growth factor expression, and accelerated disease progression.
These findings provide evidence for a beneficial role for inflam-
mation, which poses significant ramifications on immune-
targeted therapies in ALS.
CNS Inflammatory Subsets in Transgenic SOD1G93AMice. To under-
stand cellular contributions that characterize local inflammation
in the CNS microenvironment, we examined population dynam-
ics of microglia and specific lymphocyte subsets during disease
progression. SOD1G93A, SOD1WT, and non- Transgenic (Tg)
mice were analyzed at presymptomatic (day 65), early symptom-
atic (day 100), and end-stage (day 135).
In non-Tg mice, negligible numbers of lymphocytes (CD11b-
CD45hi) were present in the spinal cord at all time-points (Fig.
1 A and B). In SOD1G93Amice, an increased lymphocyte
population was present at day 65 (Fig. 1B). This population
showed significant enlargement with disease progression (Fig.
1A, Gate C), increasing 36-fold relative to non-Tg littermates by
day 135 (Fig. 1B). The resident microglia (CD11b? CD45lo)
population expanded 1.65-fold relative to non-Tg mice by end-
stage (Fig. 1A, Gate A, Fig. 1C). The peripheral monocyte
(CD11b?CD45hi) (Fig. 1A, Gate B).
The infiltrating lymphocyte population was further character-
ized to determine respective contributions by B, T, and natural
killer cell subsets. Spinal cords showed significant accumulation
of CD4?and CD8? T cells, but not CD19? B cells (Fig. 1D).
CD4?cells were positive for pan-T cell marker CD3 and
up-regulated activation marker CD69 [supporting information
(SI) Fig. S1]. A significant natural killer cell population
(NK1.1?) also appeared in SOD1G93Aspinal cords (Fig. 1D).
Lymphocyte influx was more pronounced in the spinal cord than
not occur in non-Tg or wild-type SOD1 transgenic (SOD1WT)
mice (Table S1). Therefore, recruitment of peripheral NK and
T cells contributes significantly to neuroinflammatory popula-
tions in ALS Tg mice.
analyzed data; and I.M.C. and M.C.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.
1To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
This article contains supporting information online at www.pnas.org/cgi/content/full/
© 2008 by The National Academy of Sciences of the USA
November 18, 2008 ?
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Isolated from ALS Tg Mice. In response to neuronal injury, micro-
glia undergo morphological changes and can acquire macro-
phage or dendritic cell (DC) markers (15). These receptors play
important roles in mediating cognate interactions with CNS
We found that SOD1G93Amicroglia increased in cell size
(forward scatter) and granularity (side scatter) with disease
progression (Fig. S2). Surface levels of CD11c, a prototypic DC
by day 100 (mean fluorescence intensity [MFI]: 17.18 ? 1.187),
and high levels by day 135 (MFI: 33.90 ? 1.34). These changes
were absent in non-Tg and SOD1WTmicroglia (Fig. 2A).
DCs express CD86 (B7–2) and CD54 (ICAM-1), which bind
to T cell receptors CD28 and LFA-1, respectively. Microglia
from SOD1G93Amice significantly up-regulated CD86 and CD54
(Fig. S3 a and b). Surface levels of APC maturation markers
MHC class II, CD40, and CD80, did not increase compared to
those of non-Tg or SOD1WTmicroglia (Fig. S3 c–e). Therefore,
although SOD1 microglia acquired DC receptors, they did not
undergo classic maturation stimuli (e.g., IFN-?). Peripheral
myeloid cells did not increase CD11c or CD86, demonstrating
that DC receptor acquisition was specific to CNS (Fig. S4a).
Although SOD1G93Amicroglia acquired DC markers, their
receptor profile differed from peripheral DCs isolated from
SOD1G93Amice (Fig. S4c). Immunostaining showed significant
accumulation of CD11b? microglia in mutant SOD1 ventral
horns, site of neuronal degeneration, and not in dorsal horns,
where neurons are mainly unaffected (Fig. 2B). By day 135, the
majority of spinal cord microglia (70%) expressed DC receptors
by FACS analysis (Fig. S5). Thus, microglia acquisition of DC
receptors is significant, and may mediate interactions with spinal
cord-infiltrating T cells during disease.
To understand the contribution of inflammatory factors in
ALS, we investigated changes in gene expression in immune cells
during disease progression. Microarray analysis identified a
panel of specific factors modulated in SOD1G93Aleukocytes
(Tables S2–S5). In particular, growth factors were markedly
up-regulated, specifically osteopontin, growth hormone (GH),
and insulin-like growth factor 1 (IGF-1) (Table S2). Other
up-regulated gene families included matrix metalloproteinases
(MMP), chemokines, chemokine receptors, IFN response
genes, inflammatory mediators, and lipid homeostatic factors
CD11b magnetic bead-selected microglia (?98% purity, Fig.
S6) from spinal cord were subjected to quantitative PCR anal-
Spinal cords analyzed for resident microglia, infiltrating lymphocytes, mono-
cytes at day 65, day 100, and day 135; representative populations are labeled
show specific increases in SOD1G93Aspinal cord over time (p-values by t test).
(D) Representative lymphocyte analysis for CD4?, CD8? T cells, CD19? B cells,
and NK1.1? natural killer cells. (E) Proportional increases in specific lympho-
cyte subsets relative to total immune cells in spinal cord, brain of SOD1G93A
mice. (Error bars show SEM.)
Tg mice. (A) Spinal cord microglia were analyzed for CD11c surface levels by
FACS. SOD1G93A(G93A), but not non-Tg(NT) or SOD1WT(WT) microglia show
increases in CD11c MFI (One-way ANOVA,*, P ? 0.05;***, P ? 0.001) (B)
CD11b? microglia expressing CD11c accumulate in ventral horns, but not
dorsal horns, of SOD1G93Aspinal cord. Lumbar section at day 135 with corre-
sponding high magnification images are shown. (Scale bar, 50 ?m.)
Microglia acquire dendritic cell markers in ventral horns of SOD1G93A
www.pnas.org?cgi?doi?10.1073?pnas.0804610105Chiu et al.
yses for genes identified by microarray. IGF-1, a neuroprotective
factor for motor neurons, has been shown to extend lifespan in
mutant SOD1 mice (16, 17). IGF-1 levels were significantly
higher in SOD1G93Amicroglia presymptomatically (16.30 ? 2.79
fold, P ? 0.001), increased at symptomatic onset (114.5 ? 27.9
(554.0 ? 38.3 fold, P ? 0.0001). Such up-regulation was not
observed in SOD1WTmicroglia (Fig. 3A). Osteopontin, a secre-
tory protein linked to inflammatory and regenerative processes
in the CNS (18, 19), was significantly augmented in spinal cord
osteopontin produced by activated microglia likely play yet
unexplored roles in ALS.
Previous studies found increases in inflammatory genes TNF
and IL-6 in whole spinal cord (11, 14). In contrast, our purified
SOD1G93Amicroglia did not show significant increases in TNF-?
and surprisingly, down-regulated IL-6 expression over time (Fig.
3D and Fig. S7). Furthermore, anti-inflammatory IL-1R antag-
onist was up-regulated at all time-points (Fig. 3C). Within
SOD1G93Amicroglia samples (n ? 85), IGF-1 levels were
positively correlated with CD11c (R2? 0.844) and inversely with
levels were more pronounced in spinal cord versus brain micro-
glia, showing that microglia respond in a CNS region specific
manner (Fig. S8). Our gene expression data cumulatively point
to an unexpected neuroprotective phenotype adopted by the
immune system of SOD1G93Amice.
IGF-1, CD11c Are Stimulated by IL-4 in Mutant SOD1 Microglia. To
further elucidate the microglia phenotype in SOD1G93Aspinal
cord, we investigated whether mutant SOD1 expression could
recapitulate similar properties in vitro. N9 murine microglia cell
line was transduced with lentiviruses to express SOD1G93A,
SOD1WT, or empty vector. In absence of cytokine stimulation,
mutant SOD1 did not induce IGF-1 expression (Fig. 4A).
in microglia through the Th2 cytokine IL-4 (20, 21). To examine
whether SOD1G93Amicroglia respond in a similar manner,
transduced N9 cells were treated with IL-4. IL-4 specifically
induced IGF-1 expression and down-regulated IL-6 (Fig. 4A).
IL-4 also increased IGF-1 levels in primary adult microglia from
SOD1G93Aand non-Tg mice (Fig. 4B). Furthermore, stimulated
microglia expressed DC marker, CD11c. By FACS, Th1 cytokine
IFN- ? induced MHC class II, while Th2 cytokine IL-4 induced
CD11c levels (Fig. 4B).
Therefore, one explanation for the CD11c?IGF1?IL6- phe-
notype of microglia observed in vivo is that infiltrating T cells act
as a source of IL-4. To test this hypothesis, CNS leukocytes from
end-stage SOD1G93Amice were stimulated and IL-4 production
determined by Enzyme-linked immunosorbent spot (ELISpot).
Microglia were purified by density gradient, magnetic bead selection from
spinal cords of SOD1G93A, SOD1WTand non-Tg mice. Expression levels of (A)
IGF-1 (B) Osteopontin (C) IL-1R antagonist and (D) IL-6 were determined by
quantitative PCR. Statistical analysis between SOD1G93Aand non-Tg microglia
are by t test.
(A) N9 microglia cells, uninfected (U) or transduced with human SOD1G93A
assayed for human SOD1, IGF-1, IL-6 expression. Experiments performed in
triplicate,*, P ? 0.05;**, P ? 0.01; and***, P ? 0.001, by t test. (B) Primary
or IFN-?. IL-4 induced IGF-1 and CD11c expression by quantitative PCR. Micro-
glia display morphological changes by light microscopy. By FACS, IL-4 induces
CD11c while IFN-? induces MHC Class II surface expression; CD40 levels were
unaffected (tinted histograms, untreated microglia) (C) IL-4 ELISPOT per-
formed on CNS isolated leukocytes at day 135, stimulated with Con A (Con. A)
or untreated (UT) for 48 h; numbers of IL-4 secreting cell colonies were
determined (P value by t test).
The Th2 Cytokine IL-4, a factor in modulation of microglia response.
Chiu et al.
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IL-4 producing cells than non-Tg mice (Fig. 4C). Thus, an influx
of IL-4 producing Th2 cells may modulate microglia phenotype
during disease progression.
T Cell Deficiency Decreases Microglia Reactivity, Accelerates ALS
Disease Progression. To pinpoint the role of T cells in ALS, the
SOD1G93Atransgene was bred onto a T cell receptor ? chain
(TCR?) deficient background. Without a functional antigen
receptor, thymocyte development in TCR??/? mice is blocked
at the double negative stage (22). To eliminate confounding
influences due to strain, breeding was maintained on a congenic
C57BL/6 background. FACS analysis showed that ?? T cells
were specifically ablated, while CD19? B cells remained intact
(Fig. S9); NK cells and ?? T cells were unaffected by TCR?
deficiency (data not shown). By end-stage disease, the majority
of CD4?and CD8? T cells infiltrating the spinal cord, as
observed in SOD1G93Amice, were eliminated in SOD1G93A
TCR??/? mice (Fig. S9).
In lumbar sections, microglia reactivity for Iba1, CD11b,
CD11c, and CD68 (a marker for activated microglia), were
significantly decreased (Fig. 5 and Fig. S10–S12). GFAP?
astrocytes, however, remained prominently activated in
SOD1G93ATCR??/? spinal cords (Fig. 5A). Therefore, the
absence of T cells affected microglia but not astrocyte reactivity.
In SOD1G93Asections, immunostaining revealed that IGF-1
protein localized to CD11b? microglia and blood vessels (Fig.
5B and Fig. S11), while in SOD1G93ATCR??/? sections,
expression of IGF-1 was markedly decreased (Fig. 5B).
Deficiency in T cells led to accelerated disease progression
(Fig. 6). SOD1G93ATCR??/? mice had significantly shorter
lifespans than SOD1G93ATg (log-rank test, P ? 0.0006) and
SOD1G93ATCR??/? mice (P ? 0.0029). Disease onset did not
differ between genotypes (Fig. 6 A and B). In spinal cords, motor
neuron loss was observed earlier at day 140 in SOD1G93A
TCR??/? compared with SOD1G93Amice (Fig. S13). T cell
deficiency led to direct effects on CNS pathology and inflam-
mation. At no point in our study were confounding peripheral
defects observed in TCR??/? and SOD1G93ATCR??/? ani-
mals (see SI Text). In SOD1G93ATCR??/? mice, weight loss
and motor decline was accelerated after disease onset compared
to SOD1G93ATCR??/? littermates (Fig. 6 C and D), mainly
during the late symptomatic phase of disease [?5% weight loss]
(Fig. 6E). Therefore, ?? T lymphocytes play a significant role in
modulating an endogenous neuroprotective response in mutant
In this study, a significant beneficial component of inflammation
is described in the SOD1G93ATg mouse model of ALS. Resident
microglia and lymphocytes expanded in the CNS with disease
progression and up-regulated specific genes, including neuro-
protective factor IGF-1. T cell ablation resulted in disease
acceleration and decreased microglia reactivity. These results
illustrate a complex cellular reaction by both innate and adaptive
arms of the immune system during motor neuron degeneration.
The role of adaptive immunity is not well characterized in
chronic neurodegeneration. Earlier studies documented the
presence of T cells in ALS patients and mice by histology (10,
23). Our study extends these findings by quantifying a large
influx of lymphocytes into mutant SOD1 spinal cord, including
natural killer cells, CD4?and CD8? T cells (Fig. 1). T cells can
coordinate neuroprotective mechanisms in microglia through a
Th2 response (24, 25). In our experiments, IL-4 was detected in
spinal cord-infiltrating leukocytes; in vitro, IL-4 recapitulated
IGF-1 and CD11c expression in SOD1G93Amicroglia. We found
that spinal cord microglia increased cell surface expression of
DC receptors, which may mediate interactions with infiltrating
T cells. Our flow cytometry data extends previous findings by
immunohistochemistry (9). When mutant SOD1 transgene was
bred onto a T cell deficient background, microglia activation and
IGF-1 expression were decreased in vivo, demonstrating that
adaptive immunity directly affects innate immune activation in
the CNS. In facial nerve axotomy models, axonal regeneration is
dependent on both T cells and STAT6, a critical signaling
component of Th2 immunity (25). Hence, Th2 cells may be
specifically involved in endogenous protection of motor neurons.
Studies indicate that mutant SOD1 within myeloid cells,
including microglia, contributes to pathogenesis (5, 6). The
have shown higher reactive oxygen species and TNF-? produc-
tion by mutant SOD1 microglia compared to non-Tg in response
to LPS (26, 27). Although relevant to infection, however, LPS
does not normally exist in ALS patients; moreover, conditioned
media from mutant SOD1 astrocytes was toxic to motor neurons
while media derived from mutant microglia showed minimal
end-stage mice were stained for CD68 (microglia, red), GFAP (astrocytes, green) and imaged by confocal microscopy. In the absence of T cells, CD68 fluorescence
decreases while GFAP is unchanged. (Scale bar, 20 ?m.) Cumulative analysis of CD68, and GFAP pixels in serial sections (n.s., not significant) (B) Lumbar sections
cord, microglia co-localized with expression of IGF-1 (60x magnification), and in SOD1G93ATCR?/? mice, CD11b and IGF-1 staining decreased (Ventral horn gray
the dependence of IGF-1 levels on T cells (one way ANOVA,***, P ? 0.001.)
Decreased microglia reactivity and IGF-1 expression in absence of T cells. (A) Spinal cord lumbar sections from non-Tg, SOD1G93Aand SOD1G93ATCR?/?
www.pnas.org?cgi?doi?10.1073?pnas.0804610105Chiu et al.
effect (13). It should be noted that culture studies do not fully
capture disease context, where surrounding cell environment
exerts a major influence on microglia responses. Recently,
deletion of inflammatory NADPH oxidase was shown to extend
lifespan in mutant SOD1 mice (7, 28). NADPH oxidase, which
cells, including microglia, and is also found in astrocytes (29).
In our study, analysis of microglia purified from SOD1G93A
mice demonstrated striking expression of growth factors includ-
ing osteopontin, IGF-1, and GH. Furthermore, down-regulation
of IL-6 and up-regulation of IL-1R antagonist point to an
an unexpected, beneficial role for microglia in ALS. Although
our results point to a positive effect of neuroinflammation on
motor neurons, it does not contradict existing data (5, 6).
Immunity may act as a double-edged sword, with mutant SOD1
within microglia aberrantly producing toxic factors while infil-
trating T cells induce microglia to produce neuroprotective
factors such as IGF-1. The resulting dichotomy exerts a balanced
effect on the ALS phenotype (Fig. S14).
Mutant SOD1 within microglia may cause direct effects on cell
physiology. Microglia cytorrhexis and formation of giant multinu-
cleated syncytia, indicating cellular dysfunction, has been observed
in a rat model of ALS (32). Preliminary experiments suggest that
mutant SOD1 may also interfere with microglia expression of
IGF-1 (data not shown). Immunization with glatiramer acetate,
thought to induce dendritic-like IGF1? microglia, was effective in
an Alzheimer disease model (24), but not mutant SOD1 mice (33).
activity, or to decreased microglia viability (32).
Our study contributes to emerging evidence that inflammation
nerve injury, microglia and macrophages actively participate in
axonal regeneration (34). In cerebral ischemia/reperfusion injury,
resident microglia have been shown to express IGF-1 and removal
of proliferating microglia exacerbated injury (35). In an Alzheimer
disease model, impairment of microglia recruitment increased
plaque formation and neuronal death (36). Several therapeutic
approaches in ALS are focused on nonspecific dampening of
inflammation (3). If the neuroimmune process in ALS possesses
both harmful (e.g., reactive oxygen species) and beneficial avenues
(e.g., T cell dependent growth factor production), specific ap-
proaches that block toxic signaling pathways and enhance neuro-
protection should be pursued. Future therapeutic interventions
modulating inflammation must take into account the beneficial
effect of adaptive and innate immune activation in ALS.
Materials and Methods
Mice. B6/SJL SOD1G93A, SOD1WTand non-Tg mice (Jackson Laboratories) were
analyzed at day 65, day 100, and day 135. For T cell deletion studies, B6
congenic lower copy SOD1G93Amice were bred with B6.TCR??/? mice (Jack-
son Laboratories). T cell deficiency was confirmed by PCR genotyping and
FACS analysis. Mice were maintained in full barrier pathogen-free facility
according to institutional animal care guidelines. Survival, motor and weight
loss analyses were carried out. Mice were also systematically examined for
non-neurological symptoms. For details on breeding, animal care, and symp-
tomatic analysis, see SI Text.
Flow Cytometry. Microglia and T cells were directly isolated from adult CNS;
mice were intracardially perfused with phosphate-buffer saline (PBS), spinal
cords and brains dissected separately, single cell suspensions prepared, and
run over 37%/70% discontinuous Percoll gradients (GE Healthcare). Immune
cells were collected from interface, counted, and stained on ice. Flow cytom-
etry was performed on a FACScalibur machine (BD Biosciences) and analyzed
protocols, see SI Text.
N9 microglia cell, primary adult microglia cultures, ELISPOT analysis. For
detailed protocols, see SI Text.
Immunofluorescence and Image Analysis. Primary antibodies were as follows:
Rat anti-CD68 (1:500; Serotec), rabbit anti-GFAP (1:500; Sigma), mouse anti-
hamster anti-CD11c (1:100; eBioscience). Secondary antibodies were Alexa
488 or Alexa 568 goat anti-rat, Alexa 488 goat anti-rabbit, Alexa 568 goat
anti-mouse (Invitrogen), Cy3 goat anti-hamster (Jackson Immunoresearch).
For detailed immunostaining and image analysis protocols, see SI Text.
Microarray and Real-Time PCR. Totalleukocytesfrombrainandspinalcordwere
isolated by Percoll gradient from early symptomatic, end-stage SOD1G93Amice
with non-Tg age-matched controls (n ? 5 each), pooled and lysed in TRIzol
Reagent (Invitrogen). RNA was isolated by TRIzol extraction followed by RNEasy
column purification with genomic DNA digestion (DNase) (Qiagen). RNA ampli-
fication and cDNA fragmentation was by the WT-Ovation Kit (Nugen Inc.).
Samples were hybridized to Mouse 430 2.0 GeneChips (Affymetrix), data col-
lected and analyzed by dCHIP software. Specific analysis criteria in SI Text.
For microglia purification, Percoll gradient isolated cells were subjected to
CD11b magnetic bead selection over MS selection columns (Miltenyi Biotech).
To check selection purity, cells were stained with CD11b, CD45, and analyzed
cells. (A–B) Kaplan Meier curves for survival and symptomatic onset in
SOD1G93A(males, n ? 22; females, n ? 20), SOD1G93ATCR? (m, n ? 16; f, n ?
13), SOD1G93ATCR?/? (m, n ? 13; f, n ? 11) and TCR?/? (m, n ? 7; f, n ? 10)
animals. (C) Weight loss plotted for SOD1G93ATCR? and TCR?/? littermates.
D, statistically significant time-points are indicated;*, P ? 0.05 by t test. (E)
Duration of early and late symptomatic phases of disease for
SOD1G93ATCR?/?, TCR?, and TCR?/? mice. Statistical analysis by one-way
Accelerated disease progression in mutant SOD1 mice deficient in T
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