Early Events of Alzheimer-Like Neurodegeneration in Anti-Nerve Growth Factor Transgenic Mice

Deposition of extracellular deposits of amyloid precursor protein (APP), tau hyperphosphorylation, neurofibrillary tangles and cholinergic deficits have been described in aged mice expressing anti-nerve growth factor (NGF) recombinant antibodies. We used antibodies recognising different phosphorylationdependent epitopes of the microtubule associated protein tau, microtubule associated-protein 2 (MAP2), APP, anti-β-amyloid peptide (17-24) and AD neurofibrillary tangles to study the temporal progression of neurodegeneration in anti-NGF (AD11) mice, starting from 1 month until 15 months of age. Tau hyperphosphorylation and cellular redistribution of MAP2 were observed as early as 2 months of age at the level of the entorhinal cortex and hippocampus. At subsequent ages, phosphorylated-tau immunoreactivity extended to other cortical regions. Staining for choline acetyl-transferase in basal forebrain cholinergic neurones was reduced from 2 months onwards. Staining with anti-APP antibodies revealed extracellular deposits starting from 6 months of age and increasing with age. Antiβ-amyloid peptide antibodies revealed the presence of clusters of cells in the starting from 6-months of age. βamyloid plaques were observed in the brain of 15-months old, but not at previous ages. Extracellular deposits were also revealed by a panel of silver impregnation methods, such as Gallyas, CampbellSwitzer and Bielschowsky. Protofilaments of PHFs were revealed by immunoelelctron microscopy in brains of 15-month old AD11 mice. Western blotting confirmed the progressive character of this neurodegeneration. We conclude that, in this comprehensive model for Alzheimer-like neurodegeneration, tau hyperphosphorylation in the entorhinal cortex, cytoskeletal changes and cholinergic deficits represent early events.