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Table of contents
SUMMARY
1 ABBREVIATIONS
2 INTRODUCTION
2.1 Alzheimer’s Disease
2.1.1 Aging, Dementia and AD
2.1.2 AD and its discovery
2.1.3 AD neuropathology
2.1.3.1 Senile plaques
2.1.3.2 Tau neurofibrillary tangles
2.1.4 Two types of AD
2.1.4.1 Familial AD
2.1.4.2 Sporadic AD
2.1.5 Environmental risk factors
2.1.6 APP and its processing
2.1.6.1 Function of APP
2.1.6.2 APP processing
2.1.6.3 Amyloid cascade hypothesis
2.1.6.4 Criticism and modifications to the amyloid hypothesis
2.1.7 Evolution of AD in the brain
2.1.8 Treatments
2.2 Memory formation, synaptic plasticity and modulation by A
2.2.1 Different types of memory
2.2.1.1 Declarative long term memory
2.2.2 Memory formation and its stages
2.2.2.1 Encoding, Consolidation, Storage and Retrieval
2.2.3 Episodic memory is affected in AD
2.2.3.1 Episodic-like object recognition memory in rodents
2.2.4 Hippocampus organization and pathways for memory formation
2.2.5 Basal synaptic transmission and synaptic plasticity
2.2.5.1 Glutamergic synapse
2.2.5.2 Post synaptic density
2.2.5.3 AMPAR and NMDAR
2.2.5.4 Different forms of synaptic plasticity
2.2.5.4.1 LTP
2.2.5.4.2 LTD
2.2.6 Modulatory action of A on synapse function and plasticity
2.2.6.1 Physiological conditions
2.2.6.2 Pathological conditions
2.2.7 Modulatory action of A on memory
2.2.8 Putative mechanisms of A actions at synapses
2.2.9 Mouse models of AD
2.2.9.1 Different mouse models
2.2.9.2 Tg2576
2.2.9.2.1 A accumulation
2.2.9.2.2 Memory deficits
2.2.9.3 A local injections
2.3 Stress axis
2.3.1 Stress
2.3.1.1 Definition
2.3.1.2 Acute and Chronic stress
2.3.2 Hypothalamus-Pituitary-Adrenal (HPA) axis
2.3.2.1 CORT release
2.3.2.2 Effect of CORT on thymus
2.3.2.3 ACTH release and its effect on adrenal glands
2.3.2.4 Negative feedback control of CORT
2.3.3 GRs and MRs
2.3.3.1 Gene sequence and structure of the receptors:
2.3.3.2 Functional role of the receptors
2.3.3.2.1 Membrane CORT receptors and their functions
2.3.3.2.2 Genomic action of receptors
2.3.4 Techniques to study receptor function
2.3.4.1 Different GR agonist and antagonists and their drawbacks
2.3.4.2 Genetic manipulation studies
2.3.5 Role of the hippocampus in stress/HPA axis
2.3.5.1 Effect of stress on hippocampus:
2.3.5.2 Effect of stress/CORT on synaptic plasticity
2.3.5.2.1 At intermediate CORT level/stress:
2.3.5.2.2 High CORT level/stress
2.3.5.3 Effect of CORT/ stress on memory
2.3.6 GR modulators and their use as therapeutic in AD
2.4 Link between AD and stress
2.4.1 Stress is a major environmental risk factor for AD
2.4.2 HPA axis adaptive changes in human AD patients and AD mouse models
2.4.2.1 CORT levels
2.4.2.2 ACTH levels
2.4.2.3 Stress related disorders in AD patients
2.4.3 Tau and HPA axis
2.4.4 Role of stress/CORT administration on A pathology
2.4.5 Role of GRs in AD
2.4.6 Relationship between A oligomers and GRs
2.4.7 Common link between A and CORT on the glutamatergic system
3 OBJECTIVES
4 MATERIALS AND METHODS
4.1 Animal Breeding
4.2 Genotyping
4.3 Dissection of hippocampus, thymus and adrenal glands
4.4 Biochemical Techniques
4.4.1 Estimation by ELISA
4.4.1.1 Plasma corticosterone
4.4.1.2 ACTH estimation
4.4.2 Extraction of total proteins from hippocampus
4.4.3 Immunoblotting
4.4.4 Aβ oligomer (oAβ) preparation
4.5 Local in vivo ablation of GR in GRlox/lox mice
4.5.1 Stereotaxic injections of AAV
4.5.2 Immunofluorescence staining of GR
4.5.3 Microscopy and estimation of GR intensity
4.6 Electrophysiology
4.6.1 Slice preparation
4.6.2 Field recordings by electrophysiology
4.6.2.1 To measure basal synaptic plasticity
4.6.2.2 For pharmacological studies
4.6.3 Analysis of fEPSP response:
4.7 Behaviour
4.7.1 Episodic-like object recognition memory
4.7.2 Novel Object Recognition (NOR) after local in vivo injections
4.8 Statistical analysis
5 RESULTS
5.1 Chapter 1
5.1.1 Aim: Study of HPA axis dysregulation in Tg2576 (Tg+) AD mouse model
5.1.1.1 Comparison of CORT levels in WT and Tg+ male mice at 3 and 6-month of age
5.1.1.2 Comparison of plasma ACTH levels in WT and Tg+ male mice at 4 and 6 months
5.1.1.3 Comparison of body, thymus and adrenal gland weights between WT and Tg+ male mice at 4 and 6 month of age
5.1.1.4 Quantification of GR by immunoblotting from hippocampal total protein extract in 4 months male Tg+ and WT mice
5.1.1.5 Rescue of episodic memory deficits in 4 month Tg+ male mice with GR antagonist RU486 treatment.
5.2 Chapter 2
5.2.1 Aim 2: To check the specific role of GRs in AD like phenotypes in GRlox/lox Tg+ mice.
5.2.1.1 Generation of the GRlox/lox Tg+ mice
5.2.1.2 Basic characterization of the GRlox/lox Tg + mice
5.2.1.3 Verification of AD like phenotypes in GRlox/lox Tg+ as seen in Tg+ mice.
5.2.1.4 Increased CORT levels
5.2.1.5 Exacerbated LTD phenotype
5.2.1.6 Stereotaxic injections with Cre-GFP in GRlox/lox Tg+ mice to ablate GR gene in CA1 neurons in vivo
5.3 Chapter 3
5.3.1 Aim 3: To investigate if Aß oligomers act via GRs to promote their acute synaptic effects at hippocampal synapses
5.3.1.1 Effect of oAß on levels of GR in PSD
5.3.1.2 Effect of GR Antagonist compound 13 (C13) on synaptic transmission and LTP
5.3.1.3 Effect of C13 on LTP impairment caused by oAß
5.3.1.4 Quantification of GR reduction in the CA1 of the GRlox/lox Tg- mice upon in vivo Cre-GFP transduction
5.3.1.5 Effect of GR reduction in CA1 on LTP
5.3.1.6 Effect of GR reduction in CA1 neurons on the LTP impairment caused by oA
5.3.1.7 NOR test after oAß local injections
5.4 Chapter 4
5.4.1 Discovery of -secretase APP processing pathway
5.4.2 Aim 4: Effect of CHO derived Aη- and Aη-ß peptides on LTP
6 DISCUSSION AND PERSPECTIVES
7 CONCLUSION
8 PERSONAL ACCOMPLISHMENTS
9 ANNEXE
10 REFERENCES
