Trends in Genetics
Volume 22, Issue 5, May 2006, Pages 281-289
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A decade of modeling Alzheimer's disease in transgenic mice

https://doi.org/10.1016/j.tig.2006.03.007Get rights and content

It has been over a decade since the first Alzheimer's disease (AD) transgenic mouse models were reported. These models have enabled dramatic advances in our understanding of the pathogenic mechanism in AD and of potential therapeutic approaches to tackling the inexorable clinical progression of the disease. In this article, we discuss the current status of AD mouse models and focus on recent work that has examined the development of the neuropathological lesions observed in AD (plaques and tangles). The relationship between these lesions, neurodegeneration and development of the clinical syndrome will be explored.

Section snippets

Introdution

Alzheimer's disease (AD) is characterized clinically by progressive memory loss that leads eventually to dementia. The neuropathology of AD is characterized by neuronal and synaptic loss, and by the development of two lesions; the extracellular senile plaque, which is composed mostly of amyloid formed from the amyloid β (Aβ) peptide, and the intraneuronal neurofibrillary tangle (NFT), which is composed of hyperphosphorylated forms of the microtubule associated protein tau (MAPT) [1]. Several

Transgenic mice that reproduce amyloid deposition – Aβ plaques and CAA

The first mouse models that developed amyloid plaque pathology were generated by expressing human APP containing mutations associated with early-onset AD. Games and colleagues [2] published the first transgenic mouse (PDAPP) that developed amyloid plaque pathology. PDAPP mice over-express a minigene construct encoding APPV717F and develop robust amyloid plaque pathology by 6–9 months of age [2]. Ashe et al. [3] published the Tg2576 model, which over-expresses a human APP cDNA transgene with the

Aβ and memory deficits in APP transgenic mice – the rise of the oligomer

Multiple lines of mutant APP and PSAPP transgenic have been shown to develop cognitive deficits in a variety of behavioral test paradigms, most commonly the Morris water maze 3, 27, 28, 29, 30. To examine the relationship between amyloid deposition and memory function, Westerman et al. [27] analyzed the age-dependent memory loss in Tg2576 in the Morris water maze. Spatial reference memory was shown to decline progressively from 6 months of age, corresponding with the development of

Neurodegeneration in APP and PSAPP mice

Unbiased, stereological neuronal counting has established that APP and PSAPP mouse models, despite extensive amyloid deposition in some lines, do not have widespread neuronal loss as seen in AD 12, 14, 38. In the APP23 line, limited neuronal loss in the CA1 region of the hippocampus was associated with the localized impact of dense amyloid plaques 39, 40, 41. Similar localized neuronal loss around thioflavin S (Thio-S)-positive amyloid plaques has also been reported in double transgenic PSAPP

Transgenic mice that reproduce MAPT pathology – a link to neuronal cell death

To examine the role of MAPT in AD and other tauopathies, mouse models have been developed, through expression of MAPT mutant and wild-type transgenes, that recapitulate most of the features of human neurofibrillary pathology (NFT and neuropil threads) 50, 51, 52, 53, 54 (see Box 2 for summaries of individual models). Transgenic mouse lines that develop robust neurofibrillary pathology, with both the structural and biochemical features of human NFT, also show significant neuronal loss in

Transgenic mouse models that develop amyloid plaques and NFT

Given that mutations in APP and PSEN1 cause AD with abundant NFT, it is unclear why mice expressing the mutant human APP and PSEN1 transgenes fail to develop detectable NFTs. Therefore, it is important to understand the extent to which Aβ and MAPT pathologies interact during the development of AD.

Aggressive experimental approaches involving crosses of mutant APP, PSEN1 and MAPT mice have helped us to understand this interaction. Lewis and colleagues [63] crossed mutant APP and MAPT (JNPL3)

Concluding remarks – the relationship between Aβ, MAPT and neurodegeneration

A complete mouse model of AD has proven elusive, probably because of the short lifespan of the mouse and the nature of the relationship between Aβ accumulation and other pathological features that contribute to the complex phenotype of AD. In particular, based on results from APP and PSAPP mice, it seems likely that Aβ accumulation does not lead directly to neuronal cell death in AD but usually requires the initiation of a secondary process. This provides a simple explanation of why APP and

Acknowledgements

E.M. is supported by NIA RO1 AG022595–01 and the Mayo Foundation. M.H. is supported by NIA RO1 AG020216–01A2, NIA PO1 AG17216 and the Mayo Foundation.

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