Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein

Overexpression of mutated human amyloid precursor protein (hAPP717V-->F) un der control of the platelet derived growth factor promoter (PDAPP minigene) in transgenic (tg) mice results in plaque formation and astroglial activat ion similar to Alzheimer disease (AD). However, the extent of the neurofibr illary pathology in this model is less understood. In order to determine if those mice develop AD-like neurofibrillary pathology, vibratome sections f rom PDAPP tg mice (4- to 20-months-old) were immunolabeled with antibodies against phosphorylated tau (AT8) and phosphorylated neurofilaments (SMI 312 , TA51), and analyzed by laser scanning confocal and electron microscopy. P hosphorylated neurofilament-immunoreactive dystrophic neurites in plaques w ere first seen in mice at 10 to 12 months of age, while phosphorylated tau- immunoreactive dystrophic neurites were observed after 14 months of age. Im munoelectron microscopic analysis revealed that phosphorylated neurofilamen t immunoreactivity was diffusely distributed along filamentous aggregates ( 12-15 nm in diameter) in the plaque dystrophic neurites, and occasionally i n neuronal cell bodies. In contrast, phosphorylated tau immunoreactivity wa s observed as clusters distributed along filamentous structures accumulatin g in the dystrophic neurites and around neurotubules in the axons. However, no paired helical filaments were observed. Taken together, these studies i ndicate that the PDAPP tg model recapitulates early cytoskeletal pathology similar to that observed in AD.