Transgenic animal models of neurodegenerative diseases and their application to treatment development

Abstract

Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-β protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes β- and γ-secretase as well as vaccine therapies.