The emerging utility of animal models of chronic neurodegenerative diseases.

The two most common neurodegenerative diseases are Alzheimer's disease (AD) and Parkinson's disease (PD). The symptoms are caused by the initially selective degeneration of neuronal subpopulations involved in memory (AD) or movement control (PD). The cause of both diseases is unknown, but ageing is an inevitable risk factor. The identification of disease-associated genes was a breakthrough for the understanding of molecular mechanisms of neurodegeneration and has provided the basis for the establishment of cell culture and animal model systems, instrumental for target validation and drug screening. Familial AD is caused by mutations in the beta-amyloid precursor protein (betaAPP) and in the gene products responsible for its proteolytic processing, namely the presenilins. Transgenic mice expressing these mutant genes develop characteristic AD plaques in an age-dependent manner. A reduction of plaque burden and amelioration of cognitive decline in these animals was recently achieved by vaccination with amyloid beta-protein fibrils. The other hallmark lesion of AD, the neurofibrillary tangle, has been modelled recently in transgenic mice expressing mutant tau protein linked to frontotemporal dementia. PD is characterised by intraneuronal cytoplasmic deposits (Lewy bodies) of the PD-associated gene product alpha-synuclein. Transgenic expression of alpha-synuclein recreated hallmark features of PD in mice and fruit flies, establishing alpha-synuclein as PD-causing drug target. Moreover, environmental risk factors such as the pesticide rotenone have been used successfully to generate rodent models of PD. Lesion models of PD are being exploited for the development of experimental gene therapy and transplantation approaches.