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.