Amyloid β-Peptide: The Inside Story

The amyloid β-peptide (Aβ) plays an early and critical role in the pathogenic cascade leading to Alzheimer's disease (AD). Aβ is typically found in extracellular amyloid plaques that occur in specific brain regions in the AD and Down syndrome brain. Mounting evidence, however, indicates that intraneuronal accumulation of this peptide may also contribute to the cascade of neurodegenerative events that occur in AD and Down syndrome. A pathogenic role for intracellular Aβ is not without precedent, as it is known to be an early and integral component of the human muscle disorder inclusion body myositis (IBM). Therefore, it is plausible that intracellular Aβ may likewise induce cytopathic effects in the CNS, causing neuronal and synaptic dysfunction and perhaps even neuronal loss. Here we review recent evidence supporting a pathogenic role for intracellular Aβ in AD, Down syndrome, and IBM.