Structural and Toxic Properties of Protein Aggregates: Towards a Molecular Understanding of Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is an age-related irreversible brain disorder that progresses over 10 to 20 years. AD gradually destroys human memory and thinking skills, leads to severe loss of mental function, and eventually causes death (Querfurth and LaFerla, 2010). Normally, AD symptoms first appear after age 65. It is estimated that AD affected 36 million people globally in 2009, and the number will be more than doubled by 2050. Currently, there is no cure for AD, except few medications that can relieve AD symptoms (Brunden et al., 2009; Citron, 2004). AD is accompanied by a significant shrunk of brain tissue, which is a result of brain neuron degeneration. In the brains of AD patients, neurons are found to have lost their synaptic connections with other neurons and are unable to survive (Wenk, 2003). The synaptic failure is indeed the earliest event associated with the cognitive impairment caused by the disease (Selkoe, 2002). In addition, the brains of AD patients are characterized by the presence of two types of hystopathological hallmark lesions: amyloid plaques and neurofibrillary tangles (NFTs), which are composed of aggregated proteinaceous material (Tiraboschi et al., 2004). Although both amyloid plaques and NFTs are also present in brains of healthy individuals, the amount of these aggregates in the brains of AD patients is significantly higher. Early studies correlated neuron degeneration in AD with the formation of these insoluble protein aggregates. However, recent studies suggest that soluble protein aggregates of the same protein composition are more toxic to neurons (Rahimi et al., 2008). It has also been suggested that the insoluble aggregates actually play a beneficial role in that they sequester the toxic soluble aggregates into less toxic or non-toxic insoluble aggregates (Greenwald and Riek, 2010). At current stage, we are still trying to understand how different protein aggregates in the brain mediate neuron degeneration and lead to AD. Like any other protein activity, the neurotoxicity of protein aggregates must be associated with their specific molecular structures. Therefore, investigating the high-resolution structures of amyloid plaques, NFTs and soluble aggregates would greatly facilitate the development of diagnostic and therapeutic strategies. Here, in this chapter, we review current knowledge about the structure and toxicity of the aggregates involved in AD.