Chapter 2 Transgenic Mouse Models for APP Processing and ...

Chapter 2 Transgenic Mouse Models for APP Processing and Alzheimer’s Disease: Early and Late Defects

Tom van Dooren, Ilse Dewachter, Peter Borghgraef and Fred van Leuven Experimental Genetics Group, Department of Leuven, Belgium

Human Genetics, K.U.Leuven, B-3000

Abstract: Transgenic mice with neuronal expression of human AD-mutant APP[V717I] in their brain recapitulate robustly the amyloid pathology as seen in Alzheimer’s disease (AD) patients. The AD related pathological phenotype consisting of amyloid plaques and vascular amyloid pathology, develop progressively and relative late in ageing APP transgenic mice, between 10 and 15 months of age. In contrast to the late - and clinically irrelevant - amyloid plaque-pathology, the early cognitive defects and behavioural features are clinically more interesting. This review discusses the generation and in depth phenotypic characterization of both aspects of the APP[V717I] transgenic mice. Attention is focussed on the relation of biochemical data of the different APP fragments and amyloid peptides to the formation of the typical early defects and the late parenchymal and vascular amyloid depositions. The APP[V717I] transgenic mice are a perfect model to characterize and investigate early biochemical and cognitive aspects and a potential resource to define pathological interactions of different factors known to be involved in AD. Finally, any therapeutic intervention can be directly tested and explored in these transgenic mice as excellent pre-clinical models Key words:

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Transgenic mice, Alzheimer’s disease (AD), amyloid-plaque-pathology.

INTRODUCTION: GENETICS AND PATHOLOGICAL FEATURES OF ALZHEIMER’S DISEASE

Alzheimer patients are characterized by mostly a-typical clinical features during life and by very typical pathological lesions in their brain, observed

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post-mortem: extra-cellular amyloid deposited as parenchymal plaques and vascular angiopathy, in addition to intra-cellular neurofibrillary tangles. Because of the ill-defined and largely unknown relations between the clinical and pathological problems on the one hand, and between both pathological lesions on the other hand, this chapter will first concentrate on the brain pathology and its robust recapitulation in transgenic mouse brain. Those late defects will then be related and traced back to early defects, mainly referring to behavioral and cognitive aspects that are obvious even at the "pre-amyloid" stage of the disease in APP transgenic mice. Inherited familial forms of AD are very rare (