Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model: = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell
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| Main Author: | |
|---|---|
| Format: | Thesis/Dissertation Book |
| Language: | English |
| Published: |
Erlangen ; Nürnberg
2019
|
| Subjects: | |
| Links: | http://d-nb.info/1191297691/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=031519915&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| Physical Description: | X, 221 Seiten Illustrationen, Diagramme 30 cm |
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MARC
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| 003 | DE-604 | ||
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| 015 | |a 19,H08 |2 dnb | ||
| 016 | 7 | |a 1191297691 |2 DE-101 | |
| 020 | |c Broschur | ||
| 035 | |a (OCoLC)1119016851 | ||
| 035 | |a (DE-599)DNB1191297691 | ||
| 040 | |a DE-604 |b ger |e rda | ||
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| 044 | |a gw |c XA-DE | ||
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| 084 | |a 616.3 |2 sdnb | ||
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| 100 | 1 | |a Plank, Anne-C. |e Verfasser |4 aut | |
| 245 | 1 | 0 | |a Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model |b = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |c vorgelegt von Anne-Christine Melanie Plank |
| 246 | 1 | 3 | |a Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |
| 246 | 1 | 1 | |a Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |
| 264 | 1 | |a Erlangen ; Nürnberg |c 2019 | |
| 300 | |a X, 221 Seiten |b Illustrationen, Diagramme |c 30 cm | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |b Dissertation |c Friedrich-Alexander-Universität Erlangen-Nürnberg |d 2019 | ||
| 650 | 0 | 7 | |a Glutaminyl-Peptid-Cyclotransferase |0 (DE-588)4796106-5 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Knockout |g Molekulargenetik |0 (DE-588)4671699-3 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Huntington-Chorea |0 (DE-588)4026223-6 |2 gnd |9 rswk-swf |
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
| 689 | 0 | 0 | |a Huntington-Chorea |0 (DE-588)4026223-6 |D s |
| 689 | 0 | 1 | |a Glutaminyl-Peptid-Cyclotransferase |0 (DE-588)4796106-5 |D s |
| 689 | 0 | 2 | |a Knockout |g Molekulargenetik |0 (DE-588)4671699-3 |D s |
| 689 | 0 | |5 DE-604 | |
| 856 | 4 | 2 | |m B:DE-101 |q application/pdf |u http://d-nb.info/1191297691/04 |3 Inhaltsverzeichnis |
| 856 | 4 | 2 | |m DNB Datenaustausch |q application/pdf |u http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=031519915&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |3 Inhaltsverzeichnis |
| 943 | 1 | |a oai:aleph.bib-bvb.de:BVB01-031519915 | |
Record in the Search Index
| _version_ | 1819335853892173824 |
|---|---|
| adam_text | TABLE
OF
CONTENTS
TABLE
OF
CONTENTS
....................................................................................................................................
V
ABBREVIATIONS
............................................................................................................................................
IX
1
SUMMARIES
............................................................................................................................................
1
1.1
S
UMMARY
.........................................................................................................................................
1
1.2
ZUSAMMENFASSUNG
......................................................................................................................................................................
3
2
INTRODUCTION
......................................................................................................................................
5
2.1
H
UNTINGTON
DISEASE
........................................................................................................................
5
2.1.1
GENERAL
AND
CLINICAL
ASPECTS
....................................................................................................5
2.1.2
NEUROPATHOLOGICAL
FEATURES
OF
HD
.......................................................................................
7
2.1.3
THE
BACHD
MOUSE
AS
A
RODENT
MODEL
OF
HD
......................................................................
10
2.1.4
THE
ROLE
OF
THE
CHAPERONE
AB-CRYSTALLIN
IN
HD
....................................................................
11
2.2
GLUTAMINYL
CYCLASES
AND
THEIR
ROLE
IN
DISEASE
........................................................................................................
14
2.2.1
GLUTAMINYL
CYCLASE
AND
ITS
ROLE
IN
ALZHEIMER S
DISEASE
.......................................................14
2.2.2
THE
ROLE
OFISOQC
AND
ITS
SUBSTRATE
CCL2
IN
INFLAMMATORY
PROCESSES
................................
16
2.3
I
NFLAMMATION
IN
HD
...................................................................................................................
18
2.3.1
ASPECTS
OF
NEUROINFLAMMATION
IN
NEURODEGENERATIVE
DISORDERS
........................................
18
2.3.2
NEUROINFLAMMATION
IN
HD
......................................................................................................
19
2.3.3
ALTERATIONS
IN
THE
FUNCTIONS
OF
THE
PERIPHERAL
IMMUNE
SYSTEM
.........................................
20
2.4
T
HERAPEUTIC
APPROACHES
IN
HD
...................................................................
22
3
HYPOTHESIS
AND
AIM
OF
THESIS
.....................................................................................................25
4
ANIMALS,
METHODS
AND
MATERIAL..............................................................................................
27
4.1
A
NIMALS
.........................................................................................................................................
27
4.1.1
ESTABLISHMENT
AND
GENOTYPING
OF
BACHD,
QC-KO,
ISOQC-KO
MICE
....................................
27
4.1.2
GENERATION
OF
BACHD/QC
7
AND
BACHD/ISOQC
7
MICE
........................................................
27
4.1.3
BACKCROSSING
OF
BACHD
MICE
TO
THE
C57BL/6N
GENETIC
BACKGROUND
.................................
29
4.1.4
HOUSING
CONDITIONS
AND
GENERAL
PROCEDURES
........................................................................
29
4.2
P
HARMACOLOGICAL
INTERVENTION
IN
BACHDXC57BL/6N
MICE
.....................................................30
4.2.1
COMPOUND,
DRUG
ADMINISTRATION
...........................................................................................
30
4.2.2
FIRST
TOLERABILITY
TEST
OFPBDX:
0.24,
0.8
AND
2.4
G/KGFOOD
PELLETS
....................................
30
4.2.3
CHRONIC
TREATMENT
OF
BACHD
MICE
WITH
2.4
G
PBDX/KG
FOOD
PELLETS
(LOW
DOSE)
..............
31
4.2.4
SECOND
TOLERABILITY
TEST
OF
PBDX:
4.8
AND
7.2
G/KGFOOD
PELLETS
.........................................
32
4.2.5
CHRONIC
TREATMENT
OF
BACHD
MICE
WITH
7.2
G
PBDX/KG
FOOD
PELLETS
(HIGH
DOSE)
............
33
4.3
B
EHAVIORAL
PHENOTYPING
..............................................................................................................34
4.3.1
GENERAL
HEALTH,
BODY
WEIGHT
................................................................................................
34
4.3.2
MOTOR
FUNCTION
........................................................................................................................
35
4.3.3
PSYCHIATRIC
ASPECTS
...................................................................................................................
38
4.3.4
COGNITION:
OBJECT
RECOGNITION
TEST.
........................................................................................
40
4.3.5
SENSORIMOTOR
GATING
..............................................................................................................
41
4.3.6
AUTOMATED
PHENOTYPING
........................................................................................................
42
4.4
B
IOCHEMICAL
ANALYSES
..................................................................................................................
45
4.4.1
TISSUE
PREPARATION
.................................................................................................................
45
V
4.4.2
ANALYSIS
OF
MRNA
EXPRESSION
.................................................................................................
45
4.4.3
WESTERN
BLOT
............................................................................................................................
49
4.4.4
IMMUNOHISTOCHEMISTRY
..........................................................................................................
51
4.4.5
DETECTION
OF
SOLUBLE
HTT
AND
MHTT
IN
CNS
TISSUE
VIA
TR-FRET
..........................................
53
4.4.6
MEASUREMENT
OF
SERUM
CCL2
LEVELS
VIA
ELISA
......................................................................
54
4.4.7
BLOOD
PARAMETER
ANALYSIS
......................................................................................................
55
4.5
S
TATISTICAL
ANALYSES
............................................................................................................................
55
5
RESULTS
.................................................................................................................................................57
5.1
P
HENOTYPING
OF
THE
BACHD/
ISO
QC-KO
AND
BACHD/QC-KO
LINE
................................................
57
5.1.1
GENERAL
HEALTH
AND
CHANGES
IN
BODY
WEIGHT
GAIN
................................................................
57
5.1.2
MOTOR
FUNCTION
........................................................................................................................
59
5.1.3
PSYCHIATRIC
ASPECTS
..................................................................................................................
72
5.1.4
COGNITION
.................................................................................................................................
80
5.1.5
SENSORIMOTOR
GATING
...............................................................................................................
82
5.1.6
AUTOMATED
PHENOTYPING
........................................................................................................
88
5.2
P
HENOTYPING
OF
PBDX-
TREATED
MICE
...........................................................................................
105
5.2.1
FIRST
TOLERABILITY
TEST
OFPBDX:
0.24,
0.8
AND
2.4
G
PBDX/KG
FOOD
....................................
105
5.2.2
CHRONIC
TREATMENT
OF
BACHDXC57BL/6N
MICE
WITH
2.4
G
PBDX/KG
FOOD
......................
108
5.2.3
SECOND
TOLERABILITY
TEST
OFPBDX:
4.8
AND
7.2
G
PBDX/KG
FOOD
PELLETS
.............................
119
5.2.4
CHRONIC
TREATMENT
OF
YOUNG
BACHD
MICE
WITH
7.2
G
PBDX/KG
FOOD
................................
124
5.3
A
NALYSIS
OF
HD-
RELATED
MOLECULAR
ALTERATIONS
.......................................................................
130
5.3.1
ANALYSIS
OF
MRNA
EXPRESSION
LEVELS
....................................................................................
130
5.3.2
SEMI-QUANTITATIVE
ANALYSIS
OF
PROTEIN
EXPRESSION
LEVELS
VIA
WESTERN
BLOT
.......................
137
5.3.3
SEMI-QUANTITATIVE
ANALYSIS
OF
PROTEIN
EXPRESSION
LEVELS
VIA
IHC
......................................
141
5.3.4
ASSESSMENT
OF
SOLUBLE
TOTAL
AND
MUTANT
HTT
LEVELS
IN
CNS
SAMPLES
...............................
147
5.3.5
ASSESSMENT
OF
CCL2
LEVELS
IN
SERUM
OF
BACHD/ISOQC-KO
MICE
.......................................
149
5.3.6
ASSESSMENT
OF
HEMATOLOGICAL
PROFILES
AND
CLINICAL
CHEMISTRY
PARAMETERS
......................
150
5.4
S
UMMARYTABLES
........................................................................................................................154
5.4.1
SUMMARY
OF
PHENOTYPING
RESULTS
.......................................................................................
154
5.4.2
SUMMARY
OF
FINDINGS
ON
HD-RELATED
MOLECULAR
ALTERATIONS
.............................................
157
6
DISCUSSION.......................................................................................................................................
159
6.1
I
MPACT
OF
QC
AND
/
OR
ISO
QC
INACTIVATION
ON
GENERAL
HEALTH
,
BODY
WEIGHT
,
METABOLISM
AND
LOCOMOTOR
ACTIVITY
.................................................................................................................................................................................
160
6.1.1
ISOQC
KNOCK-OUT
AMELIORATED
BODY
WEIGHT
AND
ACTIVITY
LEVELS
IN
BACHD
MICE
..............
161
6.1.2
QC
KNOCK-OUT
HAD
A
SEX-
AND
GENOTYPE-DEPENDENT
EFFECT
ON
BODY
WEIGHT
AND
DID
NOT
ATTENUATE
THE
HYPOACTIVE
PHENOTYPE
OF
FEMALE
BACHD
MICE
.......................................................
163
6.1.3
PHARMACOLOGICAL
INHIBITION
OFQC/ISOQC
HAD
A
DOSE-
AND
SEX-DEPENDENT
EFFECT
ON
BODY
WEIGHT,
ACTIVITY
AND
METABOLISM
......................................................................................................
165
6.2 I
MPACT
OF
QC
AND
/
OR
ISO
QC
INACTIVATION
ON
MOTOR
FUNCTION
.................................................
170
6.2.1
ISOQC
KNOCK-OUT
AND
PHARMACOLOGICAL
INHIBITION
OF
QC/ISOQC
ATTENUATED
ROTAROD
DEFICITS
IN
MALE
BACHD
MICE
..........................................................................................................................
170
6.2.2
ISOQC
AND
QC
KNOCK-OUT
ATTENUATED
DISTINCT
GAIT
ABNORMALITIES
IN
BACHD
MICE
..........
171
6.3
I
MPACT
OF
QC
AND
/
OR
ISO
QC
INACTIVATION
ON
PSYCHIATRIC
ASPECTS
............................................
172
VI
6.3.1
ISOQC
KNOCK-OUT
HAD
A
MILD
ATTENUATING,
PBDX
TREATMENT
NO
EFFECT
ON
ANXIETY-LIKE
BEHAVIOR
OF
BACHD
MICE
...................................................................................................................
173
6.3.2
QC
KNOCK-OUT
ATTENUATED
THE
ANXIETY-LIKE
PHENOTYPE
OF
BACHD
MICE
...........................
174
6.4
I
MPACT
OF
QC
AND
/
OR
ISO
QC
INACTIVATION
ON
COGNITIVE
ASPECTS
AND
SENSORIMOTOR
GATING
....175
6.4.1
BACHD
MICE
DID
NOT
DISPLAY
COGNITIVE
IMPAIRMENTS
IN
AN
OBJECT
RECOGNITION
TASK
........
175
6.4.2
ISOQC
KNOCK-OUT
HAD
A
MILD,
QC
KNOCK-OUT
NO
EFFECT
ON
ENHANCED
ASR
AND
PPI
DEFICITS
OF
BACHD
MICE
........................................................................................................................................
176
6.5
I
MPACT
OF
QC/
ISO
QC
INACTIVATION
ON
HD-
RELATED
MOLECULAR
ALTERATIONS
..............................
177
6.5.1
BACHD
MICE
DISPLAYED
UNALTERED
QPCT
EXPRESSION
AND
LINE-DEPENDENT
DIFFERENCES
IN
QPCTL
TRANSCRIPT
LEVELS
........................................................................................................................
177
6.5.2
CORTICAL
BDNF
LEVELS
WERE
NOT
ALTERED
IN
BACHD
MICE
OF
THE
DOUBLE
TRANSGENIC
LINES.
..178
6.5.3
LEVELS
OF
STRIATAL
MARKERS
WERE
SELECTIVELY
ALTERED
IN
FEMALE
BACHD
AND
LOW-DOSE
PBDX-
TREATED
MICE
.......................................................................................................................................
179
6.5.4
DIFFERENTIAL
EFFECT
OF
ISOQC
KNOCK-OUT
AND
QC/ISOQC
INACTIVATION
ON
MHTT
LEVELS
......
180
6.5.5
DOSE-DEPENDENT,
ENHANCING
EFFECT
OF
QC/ISOQC
INACTIVATION
ON
CRYAB
LEVELS
IN
FEMALE
BACHD
MICE
........................................................................................................................................
182
6.5.6
ISOQC
KNOCK-OUT
ATTENUATED
THE
REDUCTION
OF
CORTICAL
CRYAB
LEVELS
IN
BACHD
MICE
....
183
6.5.7
LOW-DOSE
PHARMACOLOGICAL
QC/ISOQC
INACTIVATION
ATTENUATED
INCREASED
GFAP
LEVELS
IN
MALE
BACHD
MICE
..............................................................................................................................
185
6.5.8
ISOQC
KNOCK-OUT
ATTENUATED
CCL2
EXPRESSION
IN
THE
STRIATUM
OF
BACHD
MICE
...............
186
6.5.9
ISOQC
KNOCK-OUT
NORMALIZED
THE
INCREASED
LEVEL
OF
MONOCYTES
IN
THE
BLOOD
OF
FEMALE
BACHD
MICE
........................................................................................................................................
188
7
CONCLUSION
AND
FUTURE
PERSPECTIVES
...................................................................................
189
8
REFERENCES
.......................................................................................................................................
191
9
APPENDICES
.......................................................................................................................................
209
9.1
S
UPPLEMENTARY
FIGURES
..............................................................................................................
209
9.2
L
IST
OF
FIGURES
............................................................................................................................
215
9.3
L
IST
OF
SUPPLEMENTARY
FIGURES
...................................................................................................
217
9.4
L
IST
OF
TABLES
..............................................................................................................................
218
9.5
P
UBLICATIONS
..............................................................................................................................219
9.6
A
CKNOWLEDGEMENTS
...................................................................................................................221
VII
|
| any_adam_object | 1 |
| author | Plank, Anne-C |
| author_facet | Plank, Anne-C |
| author_role | aut |
| author_sort | Plank, Anne-C |
| author_variant | a c p acp |
| building | Verbundindex |
| bvnumber | BV046139652 |
| ctrlnum | (OCoLC)1119016851 (DE-599)DNB1191297691 |
| discipline | Biologie Medizin |
| format | Thesis Book |
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| genre | (DE-588)4113937-9 Hochschulschrift gnd-content |
| genre_facet | Hochschulschrift |
| id | DE-604.BV046139652 |
| illustrated | Illustrated |
| indexdate | 2024-12-20T18:44:07Z |
| institution | BVB |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-031519915 |
| oclc_num | 1119016851 |
| open_access_boolean | |
| owner | DE-29T DE-355 DE-BY-UBR |
| owner_facet | DE-29T DE-355 DE-BY-UBR |
| physical | X, 221 Seiten Illustrationen, Diagramme 30 cm |
| publishDate | 2019 |
| publishDateSearch | 2019 |
| publishDateSort | 2019 |
| record_format | marc |
| spellingShingle | Plank, Anne-C Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell Glutaminyl-Peptid-Cyclotransferase (DE-588)4796106-5 gnd Knockout Molekulargenetik (DE-588)4671699-3 gnd Huntington-Chorea (DE-588)4026223-6 gnd |
| subject_GND | (DE-588)4796106-5 (DE-588)4671699-3 (DE-588)4026223-6 (DE-588)4113937-9 |
| title | Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |
| title_alt | Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |
| title_auth | Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |
| title_exact_search | Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |
| title_full | Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell vorgelegt von Anne-Christine Melanie Plank |
| title_fullStr | Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell vorgelegt von Anne-Christine Melanie Plank |
| title_full_unstemmed | Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell vorgelegt von Anne-Christine Melanie Plank |
| title_short | Impact of glutaminyl cyclase knock-out and pharmacological inhibition on symptoms and pathology of Huntington disease in the BACHD mouse model |
| title_sort | impact of glutaminyl cyclase knock out and pharmacological inhibition on symptoms and pathology of huntington disease in the bachd mouse model einfluss von knockout und pharmakologischer inhibition der glutaminylzyklasen auf symptome und pathologie des morbus huntington im bachd mausmodell |
| title_sub | = Einfluss von Knockout und pharmakologischer Inhibition der Glutaminylzyklasen auf Symptome und Pathologie des Morbus Huntington im BACHD Mausmodell |
| topic | Glutaminyl-Peptid-Cyclotransferase (DE-588)4796106-5 gnd Knockout Molekulargenetik (DE-588)4671699-3 gnd Huntington-Chorea (DE-588)4026223-6 gnd |
| topic_facet | Glutaminyl-Peptid-Cyclotransferase Knockout Molekulargenetik Huntington-Chorea Hochschulschrift |
| url | http://d-nb.info/1191297691/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=031519915&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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