Amyloid β accelerates phosphorylation of tau and neurofibrillary tangle formation in an amyloid precursor protein and tau double-transgenic mouse model

• Published in: Journal of neuroscience research 2010-12, Vol.88 (16), p.3547-3554
• Main Authors: Seino, Yusuke, Kawarabayashi, Takeshi, Wakasaya, Yasuhito, Watanabe, Mitsunori, Takamura, Ayumi, Yamamoto-Watanabe, Yukiko, Kurata, Tomoko, Abe, Koji, Ikeda, Masaki, Westaway, David, Murakami, Tetsuro, Hyslop, Peter St. George, Matsubara, Etsuro, Shoji, Mikio
• Format: Article
• Language: English
• Subjects: Age Factors; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Neuropathies - complications; Amyloid Neuropathies - metabolism; Amyloid Neuropathies - pathology; Animals; Brain Diseases - complications; Brain Diseases - metabolism; Brain Diseases - pathology; Disease Models, Animal; double transgenic mouse; Longitudinal Studies; Mice; Mice, Transgenic; neurofibrillary tangles; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurons - metabolism; Neurons - pathology; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - complications; Tauopathies - metabolism; Tauopathies - pathology
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22516

In Alzheimer's disease, Aβ deposits are considered the initial cardinal events that induce tauopathy secondarily. However, the relationship between Aβ amyloidosis and tauopathy has not been determined in detail. We produced double transgenic mice, 2×TgTau+/–APP+/–, by mating Tg2576 mice that exhibit Aβ amyloidosis and TgTauP301L mice that show tauopathy, and statistically analyzed the effect of Aβ accumulation on tauopathy. There was no significant difference in theprogression of Aβ accumulation among 2×TgTau+/–APP+/– and 1×TgTau−/–APP+/–, and tau accumulation among 2×TgTau+/−APP+/− and 1×Tg Tau+/–APP−/–. The appearance rates of phosphorylated tau developing in neurons and processes were significantly accelerated in 2×TgTau+/–APP+/– mice compared with those in 1×TgTau+/–APP−/– mice at 23 months of age. Accumulation of phosphorylated and confomationally altered tau and GSK3β in neuronal processes was accelerated in the white matter in 2×TgTau+/–APP+/–. The level of phosphorylated tau in the sarkosyl‐insoluble fraction was increased in 2×TgTau+/–APP+/– brains compared with that in 1×TgTau+/–APP−/– brains. Thus, Aβ amyloid partially enhances tauopathy through accumulation of insoluble, phosphorylated, and conformationally changed tau in neuronal cytoplasm and processes in the late stage. © 2010 Wiley‐Liss, Inc.