Zerr_ EU Neuro Rev_EU Neurology 08/03/2010 16:08 Page 18
Neurodegenerative Disease Alzheimer’s Disease
Figure 1: Transthyretin Levels in Cerebrospinal Fluid Table 1: Transthyretin Concentrations in Alzheimer’s
Disease Patients Compared with Healthy Controls in
30
Various Studies
Author Disease Biomarker/Methods
Gloeckner Controls (n=19) Decreased concentration of TTR in
20
et al., 2008
30
AD (n=23) AD and NPH in comparison with
CJD (n=18) controls, CJD, DLB and FTD
DLB (n=23)
FTD (n=10)
10
NPH (n=13)
Abdi et al., Group of AD TTR precursor: ratio=1.08, no change
2006
34
(n=10) versus Quantitative proteomic iTRAQ
10 control group
T
r
ansthyretin in cerebrospinal fluid (mg/l)
0
(n=10) pooled samples
AD NPH Controls CJD DLB FTD
Group of DLB TTR precursor: ratio=1.55
Disease (n=5) versus 10 Quantitative proteomic iTRAQ
control group
AD = Alzheimer’s disease; NPH = normal pressure hydrocephalus; CJD = Creutzfeldt-Jakob
(n=10) pooled samplesdisease; DLB = dementia with Lewy bodies; FTD = frontotemporal dementia.
Biroccio Group of (n=39) AD Oxidised forms of TTR are
Figure 2: Transthyretin Levels in Different Stages of
et al., 2006
35
versus control significantly less abundant in
Alzheimer’s Disease
group (n=27) the AD group
individual samples
20
Castaño Group of AD (n=43) Decreased concentration of TTR in
et al., 2006
31
versus AD; control using 2D gel electrophoresis
group (n=43) and post mortem CSF
15 individual samples
Puchades Group of AD (n=7) Decreased concentration of TTR in
et al., 2003
36
versus control group AD, quantitative proteomic
10
(n=7) pooled samples
Davidsson Group of AD (n=15) Increased concentration of TTR in
5
et al., 2002
37
versus control group AD, quantitative proteomic
(n=12) individual
samples
T
r
ansthyretin in cerebrospinal fluid (mg/l)
0
Riisoen et al., Group of AD (n=24) Decreased concentration of TTR
Minimal impairment Severe impairment
1988
13
versus control group in AD
Stages of severity in Alzheimer’s disease
(n=47) individual
samples
TTR plays an important role in keeping intra-cerebral proteins such as
Merched Group of AD (n=20) Decreased concentration of TTR
amyloid fibrils in a soluble form, and some
et al., 1998
22
control group (n=10) in AD
in vitro experiments have
demonstrated that TTR inhibits Aβ aggregation and the formation of
versus individual samples
senile plaques.
19–24
Synthetic unlabelled Aβ was incubated with CSF, TTR
AD = Alzheimer’s disease; TTR = transthyretin; NPH = normal pressure hydrocephalus;
CJD = Creutzfeldt-Jakob disease; DLB = dementia with Lewy bodies; FTD = frontotemporal
or albumin and analysed later using Western blot techniques with anti- dementia; iTRAQ = isobaric tag for relative and absolute quantitation;
TTR and anti-Ac antibodies. TTR–Aβ complexes with an apparent
CSF = cerebrospinal fluid.
molecular mass of 30kDa were observed under non-reducing
conditions,
19
which points towards high-affinity binding between those In Vivo and In Vitro Experiments
molecules. Transmission electron microscope (TEM) and light scattering In 2008, Buxbaum et al. obtained in vitro evidence of direct
analysis showed that TTR inhibited Aβ aggregation, and tryptophan (Trp) protein–protein interaction between TTR and Aβ aggregates. These
fluorescence quenching experiments also showed that full-length Aβ, findings suggest that TTR is protective because of its capacity to bind
but not non-aggregating Aβ fragments (Aβ
I–II
) and Aβ,
12–28
quench TTR’s toxic or pre-toxic Aβ aggregates in both the intracellular and
Trp fluorescence.
25
extracellular environment in a chaperone-like manner. Older APP 23
transgenic mice showed better cognitive function carrying multiple
In human CSF under physiological conditions, TTR forms soluble copies of human wild-type TTR gene. Subsequent experiments
complexes by binding to Aβ protein. An important inhibition of Aβ confirmed this effect. Expressing the APP 23 gene in the absence of
aggregation is found at a molar ratio of 1:300, which suggests that TTR mTTR, these mice showed immunohistochemical evidence of
in CSF could be the major Aβ-binding protein and protects against Aβ increased Aβ deposition relative to APP 23 animals with an active
deposition.
19,20,26
As CSF concentrations of Aβ have been reported to endogenous TTR gene. This study also demonstrated that both hTTR
increase with age,
29
the concomitant increase in TTR concentrations and mTTR bind Aβ
1–40
and Aβ
1–42
.
18
with age could be an important feature maintaining Aβ in soluble
complexes. In AD, this physiological sequestration could be imperfect Transthyretin as a Biomarker for
owing to inadequate concentrations of TTR or potentially some TTR Alzheimer’s Disease
modifications, the latter being possibly related to epithelial atrophy in Most of the literature described reduced levels of TTR in patients
the choroid plexus in patients with late-onset AD.
15
with AD. TTR levels in the CSF of patients with AD are shown to be
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