مجال
التميز
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تميز دراسي وبحثي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Reduced Zinc Transporter 3 is associated
with cognitive impairment in Lewy body dementia
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رابط إلى البحث:
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here
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تاريخ النشر:
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17/06/2014
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موجز عن البحث:
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The loss of zinc transporter 3 (ZnT3) has
been implicated in age-related cognitive decline in mice, and the protein has
been associated with plaques. We investigated the levels of ZnT3 and
postsynaptic density protein 95 (PSD95), a marker of the postsynaptic
terminal, in people with Parkinson’s disease dementia (PDD, n = 31), dementia
with Lewy bodies (DLB, n = 44), Alzheimer’s disease (AD, n = 16), and
controls (n = 24), using semiquantitative western blotting and
immunohistochemistry in 3 cortical regions. Standardized cognitive
assessments during life and semiquantitative scoring of amyloid β (Aβ), tau,
and α-synuclein at postmortem were used to investigate the relationship
between ZnT3 and PSD95, cognition and pathology. Associations were observed
between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment
(p = 0.001 and p = 0.002, respectively) and between ZnT3 levels in the
parietal cortex and cognitive impairment (p = 0.036). Associations were also
seen between ZnT3 levels in cingulate cortex and severity of Aβ (p = 0.003)
and tau (p = 0.011) pathologies. DLB and PDD were characterized by
significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in
prefrontal cortex compared with controls and AD. PSD95 levels in the parietal
cortex were found to be decreased in AD cases compared with controls (p =
0.02) and PDD (p = 0.005). This study has identified Zn2+ modulation as a
possible novel target for the treatment of cognitive impairment in DLB and
PDD and the potential for synaptic proteins to be used as a biomarker for the
differentiation of DLB and PDD from AD
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البحث (2):
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عنوان البحث:
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Depression and
Synaptic Zinc Regulation in Alzheimer Disease, Dementia with Lewy Bodies, and
Parkinson Disease Dementia
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رابط إلى البحث:
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تاريخ النشر:
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14/05/2014
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موجز عن البحث:
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OBJECTIVE:
Depression is a
common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia
(PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear
and current antidepressants do not appear to be effective. Cerebral zinc has
been implicated in depression and synaptic dysfunction. We investigated the
relationship between synaptic zinc regulation (for which zinc transporter 3
[ZnT3] is responsible) and depression in a large clinicopathologic study.
METHODS:
We examined brains
from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison
subjects without depression or dementia (N = 24). Individuals were
categorized according to the presence and severity of depression (on a scale
of 0-3) based on standardized assessments during life (principally
Neuropsychiatric Inventory). Western blotting was used to determine ZnT3
levels in Brodmann area 9 (BA9), and regression analysis was used to
determine the relationship between ZnT3 and depression.
RESULTS:
Reductions in ZnT3
in BA9 were significantly associated with elevated depression scores in the
study cohort (β = -0.351, df = 93, t = -3.318 p = 0.0004). This association
remained when only individuals with DLB, PDD, and no dementia or depression
were examined (β = -0.347, df = 78, t = -3.271, p = 0.002) or only
individuals with AD and no dementia or depression were examined (β = -0.433,
df = 37, t = -2.924, p = 0.006).
CONCLUSION:
Although decreased
zinc levels have been implicated in the genesis of depression in animal
models and in major depressive disorder in humans, this study provides the
first evidence of a role for zinc in depression in people with dementia and
highlights zinc metabolism as a therapeutic target.
Copyright © 2014
American Association for Geriatric Psychiatry. Published by Elsevier Inc. All
rights reserved.
KEYWORDS:
Alzheimer disease;
Depression; Lewy body dementia; Parkinson disease dementia; zinc
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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International Conference on Alzheimer’s
disease (ICAD)
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تاريخ الإنعقاد:
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21/07/2011
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مكان
الإنعقاد:
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Paris, France
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Impairment of the proteasome in prefrontal
cortex in Lewy body dementias.
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ملخص المشاركة:
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Background:
Dementia with Lewy bodies (DLB) and
Parkinson’s disease dementia (PDD) account for 10-20% of dementias. The
classical neuropathological and neurochemical characteristics include the
widespread presence of a-synuclein aggregates in forms of cortical Lewy
bodies (LBs). The number of LBs in cortical regions correlates with cognitive
impairment in DLB and PDD. Since the ubiquitine-proteasome system (UPS) is
the major non-lysosomal pathway for a-synuclein degradation, dysfunction of
this system could play a role in the development of a-synuclein aggregates.
Methods:
The
current study examine, mRNA expression (qRT-PCR) and protein levels (western
blotting) of a3, ß2, ß6 and Rpt6 subunits of the proteasome and the three
associated catalytic activities in post-mortem frontal cortex area (BA 9)
from DLB and PDD patients in comparison to age-matched controls. Clinical and
pathological data were available for the cases studied (duration of dementia
and Parkinsonism, MMSE score, CERAD plaque, Braak stage and a-synuclein
scores).
Results:
Protein
expression of the a3 and Rpt6 ATPase sub-unit proteins were significantly
lower in only PDD group compared with controls (-40% and -50% respectively),
although no differences in the mRNA expression of any of the subunits have
been shown between DLB, PDD and control cases. Interestingly all proteasome
activities were significantly reduced in PDD patients BA 9 extracts compared
to both controls and DLD patients (-58% for chymotrypsin-like, -48% for
trypsin-like and -71% for PGPH activities, compared to controls level). In
the combined DLB/PDD group, all these three activities and the protein level
of Rpt6 subunit correlated inversely with the duration of Parkinsonism.
Furthermore the level of Rpt6 expression negatively correlated with the
a-synuclein burden in the frontal cortex of these PDD cases (Rs -0.64, p =
0.004), and the CERAD plaque score was positively associated with
chymotrypsin-like activity (Rs 0.797, < 0.001).
Conclusions:
These
findings indicate that dysfunction of the UPS in the cerebral cortex is a
feature of PDD (but not DLB) that occurs at a later stage of the disease
process, possibly as a consequence of a-synuclein accumulation. Proteasome
activation may therefore have limited utility for the early treatment of Lewy
body dementias, however this approach may have benefits in slowing disease
progression
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المؤتمر (2):
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عنوان المؤتمر:
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ARUK: Alzheimer’ Research UK conference
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تاريخ الإنعقاد:
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March
2012
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مكان
الإنعقاد:
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Birmingham, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Effect
of proteasome and p62 protein impairment on frontal cortex and anterior
cingulate in Lewy body dementias.
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ملخص المشاركة:
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Lewy bodies are
the major pathological feature of dementia with Lewy bodies (DLB), and
Parkinson’s disease dementia (PDD) contains a core of aggregated α-synuclein,
and number correlates with cognitive impairment in DLB and PDD. Failure of
the ubiquitin-proteasome system (UPS), the major non-lysosomal pathway for
α-synuclein degradation is thought to play a major role in the formation of
Lewy bodies and the development of α- synuclein aggregates. The protein p62
may have an important role in protein aggregation because it has been shown
to be a shuttling factor for proteins to be degraded by the proteasome, and
because it is a component of aggregates from a number of neurodegenerative
diseases. In both regions, reductions in protein expression of an ATPase
subunit, RPT6, which associates directly with the 20S proteasome and is
thought
to play
multiple roles within the complex, were observed in all three groups compared
to control. Significant reductions in proteasome catalytic activities were
also observed in all three groups in both brain regions and these positively
correlated with the reduction in RPT6 expression levels. Highlighting the
potential clinical relevance, reductions in the RPT6 subunit and proteasome
catalytic activities were correlated with cognitive decline as well as
tangle, plaque and D-synuclein scores. These findings highlight a potential
the role of the proteasome in disease progression, possibly as a consequence
of aggregate formation.
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المؤتمر (3):
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عنوان المؤتمر:
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The 6th
Saudi Scientific International Conference
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تاريخ الإنعقاد:
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11th
– 14th October 2012
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مكان
الإنعقاد:
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Brunel, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Proteasome
subunit and p62 protein concentrations in frontal cortex and anterior cingulate
in Lewy body dementia
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ملخص المشاركة:
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Lewy bodies are the major
pathological feature of dementia with Lewy bodies (DLB), and Parkinson’s
disease dementia (PDD) contain a core of aggregated α-synuclein, and number
correlates with cognitive impairment in DLB and PDD. Failure of the
ubiquitin-proteasome system (UPS), the major non-lysosomal pathway for
α-synuclein degradation is thought to play a major role in the formation of
Lewy bodies and the development of α-synuclein aggregates. Using Western
blotting the current study examined levels of ±-3, ±-6 and Rpt6 subunits of
the proteasome and the shuttling protein p62 in the post-mortem frontal
cortex areas (BA 9) and anterior cingulate cortices (BA24) of DLB and PDD
patients, comparing them to age-matched controls. Clinical and pathological
data were available for the cases studied, with regard to duration of
dementia and Parkinsonism, MMSE score, CERAD plaque, Braak stage and
α-synucleinscore. In BA9, protein expression of the Rpt6 ATPase sub-unit
proteins was significantly lower in both DLB and PDD groups compared with
controls (-38%) while the 20S proteasome ±3 and ±6 were unaltered. The
expression of shuttling protein p62 was lower in the PDD group only.
Interestingly, p62 is positively correlated with Rpt6 ATPase sub-unit and
negatively correlated with duration of parkinsonism. Furthermore, in the
combined DLB/PDD group the level of Rpt6 expression negatively correlated
with the α-synucleinburden in the frontal (Rs -0.64, P = 0.004).In
BA24, the 20S proteolytic core ±6 and the 19S regulatory complex Rpt6 were
overexpressed in PDD cases only, compared to the DLB and control groups.
Interestingly, both ±6 and Rpt6 positively correlate with duration of
parkinsonism. In contrast, ±3 and p62, which inversely correlate with
duration of parkinsonism, were both overexpressed in the DLB group. These
findings indicate a difference between these two types of Lew body dementia,
especially at the anterior cingulate. The current study suggests that
dysfunction of the UPS contributes to Parkinson’s symptoms at a later stage
in disease progression, possibly as a consequence of α-synuclein
accumulation. Proteasome activation may therefore have limited utility for
the early treatment of Lewy body dementias, but the approach may have
benefits in slowing disease progression.
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المؤتمر (4):
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عنوان المؤتمر:
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ESN
conference: 5th conference on Advances in molecular mechanisms underlying
neurological disorders.
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تاريخ الإنعقاد:
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23-26/06/2014
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مكان
الإنعقاد:
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Bath,
UK
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طبيعة المشاركة:
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Poster
presentation
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عنوان المشاركة:
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Reduction
of Rpt6/S8 (a Proteasome component) is associated with cognitive decline in
LBD & AD
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ملخص المشاركة:
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Lewy
bodies are the major pathological feature of dementia with Lewy bodies (DLB),
and Parkinson’s disease dementia (PDD) and contain a core of aggregated
α-synuclein. Changes in ubiquitin proteasome system (UPS) may be an important
factor in patho- genesis. In the present study, protein expression of some
key component subunits of the UPS and two of the main three proteolytic
(chymotrypsin- and PGPH-) like activities have been determined in the frontal
cortex and the parietal cortex of DLB, PDD, Alzheimer’s disease (AD) and
matched controls. Clinical and pathological data were available for the cases
studied, including Mini-Mental State Examination (MMSE) score and
semi-quantitative scores for AD pathology (plaques and tangles) and for
α-synuclein. In both regions, reductions in protein expression of an ATPase
subunit, RPT6, which associates directly with the 20S proteasome and is
thought to play multiple roles within the complex, were observed in all three
groups compared to control. Significant reductions in proteasome catalytic
activities were also observed in all three groups in both brain regions and
these positively correlated with the reduction in RPT6 expression levels.
Highlighting the potential clinical relevance, reductions in the RPT6 subunit
and proteasome catalytic activities were correlated with cognitive decline as
well as tangle, plaque and α-synuclein scores. These findings highlight a
potential the role of the proteasome in disease progression, possibly as a
consequence of aggregate formation.
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