The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model

• Published in: Nature communications 2016-07, Vol.7 (1), p.12082-12082, Article 12082
• Main Authors: Li, Tong, Braunstein, Kerstin E., Zhang, Juhong, Lau, Ashley, Sibener, Leslie, Deeble, Christopher, Wong, Philip C.
• Format: Article
• Language: English
• Subjects: 631/378/1689/1283; 64/60; 692/308; 692/420/2780; 82/1; 82/29; 82/51; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloidosis; Animals; Brain - metabolism; Brain - pathology; Disease Models, Animal; Female; Gliosis - pathology; Health risk assessment; Humanities and Social Sciences; Humans; Male; Mice, Transgenic; Models, Biological; multidisciplinary; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Neurites - metabolism; Neurodegeneration; Pathology; Phosphorylation; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Prosencephalon - pathology; Repetitive Sequences, Amino Acid; Science; Science (multidisciplinary); tau Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12082

A central question in Alzheimer’s Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau. Alzheimer’s disease (AD) is pathologically characterized by the accumulation of neuritic plaques and neurofibrillary tangles but it is not known whether the neuritic plaque is necessary to drive the conversion of wild-type tau. Here the authors developed a mouse model in which wild-type tau is converted into pathological tau in a neuritic plaque-dependent manner.