Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease

• Published in: Neurobiology of aging 2003-12, Vol.24 (8), p.1063-1070
• Main Authors: Oddo, Salvatore, Caccamo, Antonella, Kitazawa, Masashi, Tseng, Bertrand P., LaFerla, Frank M.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid; Amyloid beta-Protein Precursor - genetics; Animals; Biological and medical sciences; Brain - metabolism; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Disease Progression; Humans; Medical sciences; Membrane Proteins - genetics; Mice; Mice, Transgenic; Mutation - genetics; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurology; Plaque, Amyloid - genetics; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Presenilin; Presenilin-1; Tangles; Tau; tau Proteins - genetics; Transgenic; β-Amyloid
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2003.08.012

Amyloid-β (Aβ) containing plaques and tau-laden neurofibrillary tangles are the defining neuropathological features of Alzheimer’s disease (AD). To better mimic this neuropathology, we generated a novel triple transgenic model of AD (3xTg-AD) harboring three mutant genes: β-amyloid precursor protein (βAPP Swe), presenilin-1 (PS1 M146V), and tau P301L. The 3xTg-AD mice progressively develop Aβ and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We find that Aβ deposits initiate in the cortex and progress to the hippocampus with aging, whereas tau pathology is first apparent in the hippocampus and then progresses to the cortex. Despite equivalent overexpression of the human βAPP and human tau transgenes, Aβ deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated.