Towards a better understanding of Alzheimer's disease: N -terminally truncated Aβ species and Alzheimer's disease pathogenesis
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Aging is the major risk factor for AD. Nearly 50% of people over the age of 85 are likely to be affected by AD (3). As the general population of the United States and other developed countries ages, Alzheimer's disease is becoming a global health and social crisis. Recent statistics indicate that 4.5 million Americans have Alzheimer's disease and 13 million could be affected by the year 2050 (4). A better understanding of the disease mechanism is crucial for developing a specific and effective intervention. Extensive studies have been performed to understand the pathological hallmarks of AD: extracellular amyloid plaques, which contain amyloid β peptides (Aβ); and intracellular neurofibrillary tangles, which contain hyperphosphorylated Tau. This dissertation describes our attempt to understand the role of N-terminally truncated Aβ especially Aβ11-40/42 in the development of AD. This pool of Aβ is not only readily detectable in AD patients' brains, but also could be generated directly by enzymes responsible for generating full length Aβ. Yet, for historical reasons, research efforts have mostly been focused on the generation, distribution and toxicity of full length Aβ. Here we performed a systematic analysis to understand the generation of Aβ11-40/42 in cell lines, their distribution in postmortem human AD/Down syndrome (DS) brain tissues and their toxicity in a transgenic mouse model. Our studies suggest that Aβ11 is an important component of AD pathology, as it is readily secreted by cells and is abundant in postmortem human brain tissues. This calls for further analysis of the role of N-terminally truncated Aβ species in the pathogenesis of AD.