, Volume 26, Issue 2-3, pp 299-316

Intracellular A-beta amyloid, A sign for worse things to come?

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In this review the authors discuss the possible neuropathological role of intracellular amyloid-β accumulation in Alzheimer’s disease (AD) pathology. There is abundant evidence that at early stages of the disease, prior to Aβ amyloid plaque formation, Aβ peptides accumulate intraneuronally in the cerebral cortex and the hippocampus. The experimental evidence would indicate that intracellular amyloid-β could originate both by intracellular biosynthesis and also from the uptake of amyloidogenic peptides from the extracellular milieu. Herein the aspects of the possible impact of intracellular amyloid-β in human AD pathology are discussed, as well as recent observations from a rat transgenic model with a phenotype of intracellular accumulation of Aβ fragments in neurons of the hippocampus and cortex, without plaque formation. In this model, the intracellular amyloid-β phenotype is accompanied by increased MAPK/ERK activity and tau hyperphosphorylation. Finally, the authors discuss the hypothesis that, prior to plaque formation, intracellular Aβ accumulation induces biochemical and pathological changes in the brain at the cellular level priming neurons to further cytotoxic attack of extracellular amyloidogenic peptides.