Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer's disease

The progressive accumulation of extracellular amyloid plaques in the brain is a common hallmark of Alzheimer's disease (AD). We recently identified a novel species of A beta phosphorylated at serine residue 8 with increased propensity to form toxic aggregates as compared to non-phosphorylated species. The age-dependent analysis of A beta depositions using novel monoclonal phosphorylation-state specific antibodies revealed that phosphorylated A beta variants accumulate first inside of neurons in a mouse model of AD already at 2 month of age. At higher ages, phosphorylated A beta is also abundantly detected in extracellular plaques. Besides a large overlap in the spatiotemporal deposition of phosphorylated and non-phosphorylated A beta species, fractionized extraction of A beta from brains revealed an increased accumulation of phosphorylated A beta in oligomeric assemblies as compared to non-phosphorylated A beta in vivo. Thus, phosphorylated A beta could represent an important species in the formation and stabilization of neurotoxic aggregates, and might be targeted for AD therapy and diagnosis.