Key Enzymes and Proteins in Amyloid-Beta Production and Clearance

Last century, in 1907, Alois Alzheimer first described the disease that now bears his name, relating a 54-year-old female case with presenile dementia. Alzheimer’s disease (AD), an irreversible progressive neurodegenerative disorder, is actually the most common form of dementia. AD affects more than 24 million people all over the world, and is predicted to double every 20 years, becoming one of the medical burdens of our days. More than 90% of AD cases are sporadic late-onset, and have a complex idiopathic aetiology. The small number of early onset AD cases, is related to hereditary monogenic defects, and has provided important clues for understanding the AD pathology (Bertram, et al. 2007). Although the available drugs are able to delay the symptoms and progression of the disease and to positively influence the quality of life of the patients, at present there is still no cure for AD. AD is characterized clinically by progressive decline in cognitive function and neuropatologically by the presence of neuropil threads and neuron loss, in addition to the molecular hallmarks of neurofibrillar tangles and neuritic (or senile) plaques in the brain. Neuritic plaques are extracellular amyloid deposits found abundantly in the hippocampus, in the neocortex and in the amygdala of AD brains. These pathological brain changes may occur 20 to 30 years prior to the onset of the clinical symptoms and the symptomatic phase of AD can last from 5 to 12 years (DeKosky and Marek 2003). The extracellular neuritic plaque deposits of amyloid were first investigated by (Glenner and Wong 1984), when they purified microvascular amyloid deposits from AD brains, and provided a partial sequence of a 4kDa subunit protein, that they named amyloid-beta (A┚) peptide. Around the same time, the hyperphosphorylated tau (p-tau), a microtubule assembly protein, was identified as the main constituent of the neurofibrillar tangles (NFTs) that accumulate inside many neurons in AD brains (Grundke-Iqbal, et al. 1986). Amyloid deposition and neurofibrillar tangles, occur with some frequency in brains of young adults with Down's syndrome (Schochet, et al. 1973). The discovery that amyloid deposits in the brain from Down syndrome were composed of A┚ peptide (Glenner and Wong 1984), as well as the cloning of the beta amyloid precursor protein (APP), with its localization to the chromosome 21