Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging Journal Article

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Authors: Means, J. C.; Gerdes, B. C.; Kaja, S.; Sumien, N.; Payne, A. J.; Stark, D. A.; Borden, P. K.; Price, J. L.; Koulen, P.
Article 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.
Journal Title: Neurochemical research
Volume: 41
Issue: 9
ISSN: 1573-6903; 0364-3190
Publisher: Unknown  
Journal Place: United States
Date Published: 2016
Start Page: 2278
End Page: 2288
Language: ENG
DOI/URL:

10.1007/s11064-016-1942-9
Notes: LR: 20161025; GR: P01 AG022550/AG/NIA NIH HHS/United States; GR: P01 AG027956/AG/NIA NIH HHS/United States; GR: P01 AG010485/AG/NIA NIH HHS/United States; GR: R01 EY022774/EY/NEI NIH HHS/United States; GR: S10 RR027093/RR/NCRR NIH HHS/United States; GR: S10 RR022570/RR/NCRR NIH HHS/United States; JID: 7613461; NIHMS792860; OID: NLM: NIHMS792860 [Available on 09/01/17]; OID: NLM: PMC4965284 [Available on 09/01/17]; OTO: NOTNLM; PMCR: 2017/09/01; 2016/01/27 [received]; 2016/04/29 [accepted]; 2016/04/27 [revised]; ppublish