Transgenic Mice Model in Alzheimer's Disease

Article excerpt

Abstract

Alzheimer's disease can either occur sporadically or be caused by inheritance of a gene mutation accompanying progressive loss of memory and general decline in cognition. The pathology of Alzheimer's disease is complex, but there are 2 hallmarks: the neuritic plaque consisting of [beta]-amyloid derived from [beta]-amyloid precursor proteins and the neurofibrillary tangles consisting of abnormally phosphorylated tau protein. Transgenic mice are used to reproduce these 2 hallmarks since they can reproduce many features of the disease. This review provides an overview of transgenic mouse models including familial Alzheimer's disease and nonhereditary Alzheimer's disease as well as emerging insights relevant to the pathogenesis and potential treatment strategies.

Key words: Alzheimer disease, Animal models, Therapy, Transgenic mice

Introduction

Alzheimer's disease (AD) is the most prevalent type of dementia. It occurs either sporadically or is caused by inheritance of a gene mutation accompanying progressive loss of memory and global cognitive decline. The pathology of AD is complex, but there are 2 hallmarks that occur abundantly in most cases. The neuritic plaque is a largely extracellular lesion consisting of [beta]-amyloid (A[beta]) released from cleaved A[beta] precursor proteins (APPs) by [alpha]-, [beta]- and [gamma]-secretase and the intracellular neurofibrillary tangles (NFTs) consist largely of abnormally phosphorylated tau protein. Neuronal and synaptic loss with reactive gliosis also occur.

A good animal model will help considerably both for understanding the relationships between various aspects of pathology and for testing therapies based upon these relationships. (1)

Hereditary Alzheimer's Disease Transgenic Animal Model

Alzheimer's Disease Genetics

Some cases of early onset AD are familial autosomal dominant (FAD) disorders caused by mutations in APP, PS1 and PS2. (2) In the late onset forms, there are no specific gene mutations associated with FAD inheritance, although specific alleles of apolipoprotein E and [beta]2 macroglobulin (A2M) are reported to be associated with increased risk for AD (Table 1). (3)

Transgenic mice that express disease-causing genes reproduce many features of the disease. These models are proving to be useful in investigations of the nature of biochemical alterations in neural tissue, the character and evolution of pathologies, and the pathogenic mechanisms.

[beta]-Amyloid Precursor Protein Mutations

The APP gene, the first AD susceptibility gene to be identified, encodes a transmembrane protein that contains 770 amino acids in its longest isoform. Mutational studies of the APP gene have identified a Glu693Gln missense mutation of the APP gene, (4) and several other missense mutations in exons 16 and 17 of the APP gene. Although a number of APP mutations have been identified, most are probably not disease causing. However, the missense mutations at codon 670/671 (Swedish mutation), at codon 692 (Flemish mutation), at codon 716, and at codon 717 are thought to be pathogenic.

The first successful transgenic mouse model with A[beta] amyloid deposition was made by Games et al. (5) These researchers took an unusual construct that included full-length human APP complementary DNA with the APP717Val(V)[right arrow]Phe(F) mutation under the control of the platelet-derived growth factor promoter, which targets expression preferentially to neurones of the cortex, hippocampus, hypothalamus, and cerebellum of transgenic animals. (6) The pathology of the mice was as striking as in patients with AD, and included extracellular A[beta] deposition, dystrophic component, gliosis, and loss of synaptic density with regional specificity resembling that of AD, although NFTs were not evident.

Hsiao et al used the hamster prion protein promoter to overexpress the human [APP. …