title: Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging.
abstract: Mouse models of neurodegenerative diseases such as Alzheimer's disease (AD) are important for understanding how pathological signaling cascades change neural circuitry and with time interrupt cognitive function. Here, we introduce a non-genetic preclinical model for aging and show that it exhibits cleaved tau protein, active caspases and neurofibrillary tangles, hallmarks of AD, causing behavioral deficits measuring cognitive impairment. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans with potentially high impact on both new basic research into pathogenic mechanisms and new translational research efforts. Tau aggregation is a hallmark of tauopathies, including AD. Recent studies have indicated that cleavage of tau plays an important role in both tau aggregation and disease. In this study we use wild type mice as a model for normal aging and resulting age-related cognitive impairment. We provide evidence that aged mice have increased levels of activated caspases, which significantly correlates with increased levels of truncated tau and formation of neurofibrillary tangles. In addition, cognitive decline was significantly correlated with increased levels of caspase activity and tau truncated by caspase-3. Experimentally induced inhibition of caspases prevented this proteolytic cleavage of tau and the associated formation of neurofibrillary tangles. Our study shows the strength of using a non-transgenic model to study structure, function and molecular mechanisms in aging and age related diseases of the brain.
authors.affiliation: Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Means
authors.affiliation: Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Gerdes
authors.affiliation: Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.|Department of Ophthalmology, Stritch School of Medicine, Loyola University Chicago, 2160 S First Ave., Maywood, IL, 60153, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Kaja
authors.affiliation: Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sumien
authors.affiliation: Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Payne
authors.affiliation: Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Stark
authors.affiliation: Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Borden
authors.affiliation: Department of Neurology and Cognitive Neuroscience, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.|School of Biological Sciences, University of Missouri-Kansas City, 5007 Rockhill Rd, Kansas City, MO, 64110, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Price
authors.affiliation: Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA. koulenp@umkc.edu.|School of Biological Sciences, University of Missouri-Kansas City, 5007 Rockhill Rd, Kansas City, MO, 64110, USA. koulenp@umkc.edu.|Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA. koulenp@umkc.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Koulen
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008569:Memory Disorders / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Age-related cognitive decline; Molecular mechanisms in brain aging; Neurofibrillary tangles; Preclinical; Tauopathy