Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer's disease

The aberrant accumulation of aggregated beta-amyloid peptides (A beta) as plaques is a hallmark of Alzheimer's disease (AD) neuropathology and reduction of A beta has become a leading direction of emerging experimental therapies for the disease. The mechanism(s) whereby A beta is involved in the pathophysiology of the disease remain(s) poorly understood. Initially fibrils, and subsequently oligomers of extracellular A beta have been viewed as the most important pathogenic form of A beta in AD. More recently, the intraneuronal accumulation of A beta has been described in the brain, although technical considerations and its relevance in AD have made this a controversial topic. Here, we review the emerging evidence linking intraneuronal A beta accumulation to the development of synaptic pathology and plaques in AD, and discuss the implications of intraneuronal beta-amyloid for AD pathology, biology, diagnosis and therapy.