Early intraneuronal Aβ deposition in the hippocampus of APP transgenic mice

Increasing evidence suggests that intraneuronal amyloid-β (Aβ) accumulation may be an early event in Alzheimer's disease (AD) pathogenesis. However direct in vivo evidence regarding initial Aβ seeding is missing. Using an APP transgenic mouse model, our sensitive immunocytochemical procedures revealed a novel intraneuronal Aβ deposition in the somas of hippocampal CAI/subiculum neurons far in advance of the occurrence of extracellular Aβ plaques. These deposits increased exponentially with age and were elevated ∼4-fold (p < 0.001) by high fat/high cholesterol diet. Aβ40 and Aβ42 were the major constituents of these deposits and were co-localized with lysosomal markers. Our results are consistent with the notion that the earliest Aβ deposition occurs intraneuronally, prior to extracellular amyloid plaque formation.