Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy.
Neurofibrillary tangles form in a specific spatial and temporal pattern in Alzheimer's disease. Although tangle formation correlates with dementia and neuronal loss, it remains unknown whether neurofibrillary pathology causes cell death. Recently, a mouse model of tauopathy was developed that reversibly expresses human tau with the dementia-associated P301L mutation. This model (rTg4510) exhibits progressive behavioral deficits that are ameliorated with transgene suppression. Using quantitative analysis of PHF1 immunostaining and neuronal counts, we estimated neuron number and accumulation of neurofibrillary pathology in five brain regions. Accumulation of PHF1-positive tau in neurons appeared between 2.5 and 7 months of age in a region-specific manner and increased with age. Neuron loss was dramatic and region-specific in these mice, reaching over 80% loss in hippocampal area CA1 and dentate gyrus by 8.5 months. We observed regional dissociation of neuronal loss and accumulation of neurofibrillary pathology, because there was loss of neurons before neurofibrillary lesions appeared in the dentate gyrus and, conversely, neurofibrillary pathology appeared without major cell loss in the striatum. Finally, suppressing the transgene prevented further neuronal loss without removing or preventing additional accumulation of neurofibrillary pathology. Together, these results imply that neurofibrillary tangles do not necessarily lead to neuronal death.
Spires
Tara L
TL
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown 02129, USA. tspires@partners.org
Orne
Jennifer D
JD
SantaCruz
Karen
K
Pitstick
Rose
R
Carlson
George A
GA
Ashe
Karen H
KH
Hyman
Bradley T
BT
D000375:Aging; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000473:pathology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D020868:Gene Silencing; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009454:Neurofibrils / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014157:Transcription Factors; D056427:t-Complex Genome Region; D016875:tau Proteins
D015415:Biomarkers; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; C533390:Phf1 protein, mouse; C054369:MAPT protein, human; D016875:tau Proteins