Intracellular A? and its Pathological Role in Alzheimer's Disease: Lessons from Cellular to Animal Models

Accumulation of intraneuronal amyloid-β peptide (Aβ) appears to be an early event in Alzheimer's disease (AD), suggesting its important role in the neurodegenerative process of AD. It is indicated that intracellular Aβ originates from a portion of Aβ, which is not secreted and consequently remains intracellular, or alternatively from the secreted Aβ, which is internalized into intracellular Aβ pool. A number of cell and transgenic animal models are established to study the pathological role of intracellular Aβ, and to screen for drugs against Aβ aggregation and associated toxicity. Aβ aggregates, particularly oligomers, may lead to synaptic dysfunction and neuronal loss. Screened from high-throughput methods, a number of cellpermeable agents reduce the aggregation of intracellular Aβ and antagonize its cytotoxicity by inhibiting the formation of Aβ oligomers in vivo. The multi-functional roles of Aβ in alternate pathways and associated clinical implications for AD treatment are also discussed.