[Involvement of beta-amyloid in the etiology of Alzheimer's disease]

Takami Tomiyama
Brain and Nerve, Shinkei Kenkyū No Shinpo 2010, 62 (7): 691-9
Amyloid beta-peptide (Abeta) is a key molecule in Alzheimer disease (AD). Cerebral deposition of Abeta was earlier thought to initiate the pathological cascade of AD, including the formation of senile plaques and neurofibrillary tangles, neuronal loss, and dementia. According to the classical amyloid hypothesis, the aggregation of Abeta into insoluble beta-sheet fibrils plays an important role in its neurotoxicity. However, this hypothesis is paradoxical: The concentrations of Abeta required for fibrillization and neurotoxicity are higher than its physiological concentrations. Cognitive decline in AD patients is not correlated with the levels of senile plaque formation or insoluble Abeta formation; instead it correlates with the levels of synapse loss and the levels of soluble Abeta. These observations suggest the existence of soluble toxic forms of Abeta in AD brains; these forms have recently been identified to be oligomeric assemblies of Abeta. At present, AD is believed to begin with synaptic dysfunction caused by soluble Abeta oligomers. This hypothesis termed the oligomer hypothesis, is based on the following observations: The levels of Abeta oligomers are high in AD brains. Exogenous Abeta oligomers at physiological concentrations cause synaptic and cognitive dysfunction in vivo and synapse loss and neuronal death in vitro. Furthermore, we observed that the E693delta mutation in the amyloid precursor protein found in AD patients causes disease by increasing the formation of Abeta oligomers without inducing the formation of Abeta fibrils or senile plaques. Currently, senile plaque formation is thought to occur in order to protect neurons from the toxicity of diffusible Abeta oligomers by sequestering them into deposits. Thus, soluble Abeta oligomers play a more important role in the etiology of AD insoluble Abeta fibrils.

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