Generation & Validation of Double Transgenic Mice in
Vivo Model for the Synergism between Amyloid & Tau
Pathology in Alzheimer's Disease
Acta Biomedica Lovaniensia, No. 410

By David Muyllaert
December 2007
Leuven University Press
Distributed By Coronet Books
ISBN: 9789058676535
195 pages, Illustrated, 6 1/8 x 9 1/2"
$147.50 Paper Original

Chapter 1 : General introduction

1.1 Alzheimer's disease
1.1.1 Progression of AD-associated cortical lesions
1.1.2 Clinical features and early diagnosis
1.1.3 Pathological hallmarks of Alzheimer's disease
1.1.4 Genetics of alzheimer's disease
1.2 Amyloid Precursor Protein
1.2.1 Transcription to expression
1.2.2 Proteolytic processing of APP
1.2.3 Functional properties
1.3 Tau-protein
1.3.1 Functions of protein tau in neuronal development
1.3.2 Structure and regulation
1.3.3 Tau binding to microtubules
1.3.4 Taupathies
1.4 Kinases
1.4.1 GSK-3-beta
1.4.2 Cdk5
1.5 Transgenic mice

Chapter 2 : Rationale and Aim

Chapter 3: Materials and Methods

3.1 Generation of transgenic mice
3.1.1 Molecular CaMKIIalpha.Tau(P301L) construct strategy
3.1.2 Molecular pBi.p25 construct strategy
3.1.3 Transgenic and microinjection procedures
3.2 Genotyping the transgenic mouse models
3.3 Imminohistochemical, histological and biochemical analyses
3.3.1 Immunohistochemical tissue preparation
3.3.2 Immunohistochemistry of amyloid load and gliosis
3.3.3 Histology
3.3.4 Biochemical tissue preparation
3.4 Primary hippocampal neuronal culture
3.5 Antibodies
3.6 Behavior and cognition

Chapter 4: Neurodegeneration and neuroinflammation in cdk5/p25 inducible mice, a model for hippocampal sclerosis and neocortical degeneration

4.1 Introduction
4.2 Results
4.2.1 Generation of inducible p25 mice: early lethality and initial characterization
4.2.2 Progressive forebrain atrophy due to neurodegeneration in p25-on mice
4.2.3 Mechanism of neurodegeneration in p25-on mice
4.2.4 Progressive microgliosis and astrogliosis in p25-on mice
4.2.5 Switching off p25 expression stops neurodegeneration and inflammation
4.2.6 Primary hippocampal neurons activate microglia in culture
4.3 Discussion

Chapter 5: Neurodegeneration in p25 mice: behaviour, cognition and neuroinflammation

5.1 Introduction
5.2 Results and discussion
5.2.1 Motor performance and cognition of p25-on mice
5.2.2 Progressive forebrain atrophy: unaltered cortex layering
5.2.3 Pioglitazone does not curb neuroinflammation

Chapter 6: Generation and characterization of CaMKII - Tau-P301L mice and bigenic combinations with APP-V717I, GSK-3beta and p25-deficiency

6.1 Introduction
6.2 Results
6.2.1 Generation of CaMKII-Tau-P301L transgene mice with expression in forebrain neurons
6.2.2 Characterisation of CaMKIIalpha-Tau-P301L transgene mice
6.2.3 Characterisation of CaMKIIalpha-Tau-P301L x Thy1.APP-V717I bigenic mice 6.2.4 Characterisation of CaMKIIalpha-Tau-P301L x Thy1.GSK-3beta(S9A) bigenic mice
6.2.5 Characterisation of CaMKIIalpha-Tau-P301L x p35-/-bigenic mice
6.3 Discussion

Chapter 7: Generation and characterization of CaMKII - Tau-P301L mice and bigenic combinations with APP-V717I, GSK-3beta and p25-deficiency

7.1 Introduction
7.2 Results
7.2.1 APP-V717I x Tau-P301L bigenic mice with combined AD-like pathology
7.2.2 GSK-3beta(S9A) x Tau-P301L bigenic mice with dramatic tauopathy
7.2.3 Defects in behavior and cognition and clinical features 7.2.4 Increased survival is related to alleviated brainstem tauopathy
7.2.5 Biochemical analysis of tau and GSK-3 isozymes
7.2.6 Amyloid activates both GSK-3 isozymes by tyrosine phosphorylation
7.3 Discussion

Chapter 8: GSK-3beta and lithium ions, and the connection to axonopathy

8.1 Introduction
8.2 Results and discussion






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