Relevance of Transgenic Mouse Models to Human Alzheimer Disease

Frank M. LaFerla,Anna Parachikova,Kim N. Green,Debbi A. Morrissette

doi:10.1074/jbc.r800030200

Frank M. LaFerla, Anna Parachikova + Show 2 more

Open Access

https://doi.org/10.1074/jbc.r800030200

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Abstract

During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.

Highlights

The most common cause of dementia, AD2 accounts for 60 –70% of all dementia cases and afflicts Ͼ15 million individuals worldwide
The length of A␤ can vary, but a 42-amino acid variant is considered neurotoxic because of its propensity to readily aggregate into oligomers and fibrils
In vitro experiments and transgenic mice have shown us that the aggregation state of A␤ is crucial, that it can accumulate intraneuronally, and that it can mediate a diverse range of pathological effects on cellular function [2]

Summary

Pathological Hallmarks of AD

Definitive diagnosis of AD occurs during post-mortem examination upon detection of two hallmark pathologies. Mutations in the gene for tau (MAPT) are not associated with AD but cause FTDP-17 (frontal temporal dementia with parkinsonism 17), showing that disruption of tau function directly leads to neurodegeneration Besides these two hallmark lesions, other reactive processes occur such as inflammation [5] and additional disturbances in cellular function through calcium dyshomeostasis [6] and oxidative stress [7], which cumulatively cause marked cortical and hippocampal neuronal and synaptic loss. Transgenic mice that overproduce A␤ mimic many facets of the human disease and lend credence to the amyloid cascade hypothesis These mice have allowed us to understand more about the course of the disease and how the pathology affects the local brain environment to cause cognitive deterioration and to explore potential therapeutic avenues. These mice do not mimic several aspects of the human disorder, these differences have led to some of the more intriguing discussions about human AD

Modeling Amyloid Pathology in Mice

Modeling Tau Pathology in Mice

Synaptic Defects

Future Directions