Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines.
Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1) cerebrospinal fluid (CSF) AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2) structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG), and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3) cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines and standards for models of AD and other neurodegenerative disorders.
Department of Pathology, University of Washington, Seattle, WA, USA.
C Dirk
CD
Keene
Department of Pathology, University of Washington, Seattle, WA, USA.
Martin
M
Darvas
Geriatrics Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care Systems, Seattle, WA, USA.|Division of Gerontology and Geriatrics Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
Brian
B
Kraemer
Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
Denny
D
Liggitt
Department of Pathology, University of California at San Diego, La Jolla, CA, USA.|Scripps Research Institute, La Jolla, CA, USA.
Christina
C
Sigurdson
Department of Pathology, University of Washington, Seattle, WA, USA.|Department of Comparative Medicine, University of Washington, Seattle, WA, USA; wladiges@u.washington.edu.
Warren
W
Ladiges
Alzheimer's disease; NIA-AA guidelines; mouse models of Alzheimer's disease; neuropathological validation