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. Alzheimer’s disease (AD) is characterized by cognitive impairment, progressive degeneration of neuronal populations in the neocortex and limbic system, and formation of amyloid plaques and neurofibrillary tangles. Amyloid-β (Aβ) is the product of proteolysis of amyloid precursor protein (APP) by β and γ-secretase enzymes. The neurodegenerative process in AD initiates with axonal and synaptic damage and is associated with progressive accumulation of toxic Aβ oligomers in the intracellular and extracellular space. In addition, neurodegeneration in AD is associated with alterations in neurogenesis. Aβ accumulation is the consequence of an altered balance between protein synthesis, aggregation rate, and clearance. Identification of genetic mutations in APP associated with familial forms of AD and gene polymorphisms associated with the more common sporadic variants of AD has led to the development of transgenic (tg) and knock out rodents as well as viral vector driven models of AD. While APP tg murine models with mutations in the N- and C-terminal flanking regions of Aβ are characterized by increased Aβ production with plaque formation, mutations in the mid-segment of Aβ result in increased formation of oligomers, and mutations toward the C-terminus (E22Q) segment results in amyloid angiopathy. Similar to AD, in APP tg models bearing familial mutations, formation of Aβ oligomers results in defective plasticity in the perforant pathway, selective neuronal degeneration, and alterations in neurogenesis. Promising results have been obtained utilizing APP tg models of AD to develop therapies including the use of β- and γ-secretase inhibitors, immunization, and stimulating neurogenesis.
