%0 Journal Article
%T Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines
%A Brian Kraemer
%A C. Dirk Keene
%A Christina Sigurdson
%A Denny Liggitt
%A Martin Darvas
%A Warren Ladiges
%J Archive of "Pathobiology of Aging & Age Related Diseases".
%D 2016
%R 10.3402/pba.v6.32397
%X 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 A¦Â and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of A¦Â 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 A¦Â 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 A¦Â 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
%K Alzheimer's disease
%K mouse models of Alzheimer's disease
%K neuropathological validation
%K NIA-AA guidelines
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912600/