Aged Rodents Provide a Model to Study the Molecular Mechanisms of Age-related Cognitive Decline and Early Stage Alzheimer's Disease Pathology
Shannon Leslie1, Dibyadeep Datta2, Johanna Crimins2, Christopher van Dyck1,2,3, Angus Nairn1, Amy Arnsten1,2
1Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; 2Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA; 3Department of Neurology, Yale School of Medicine, New Haven, CT, USA
Late-onset Alzheimer's disease (LOAD) is a growing public health crisis and new models are needed to study the disease in the absence of genetic factors. According to the Alzheimer's Association, deterministic genes are responsible for only 1% of AD cases while age represents the largest risk factor for the disease.1 Thus, we began to study the effects of aging on molecular pathways that contribute to tau modifications indicative of Alzheimer's disease-like pathology. Our labs recently published compelling evidence that the aged rhesus macaque presents Braak stage III/IV AD-like pathology in addition to previously noted age-related cognitive decline.2 We have since discovered that rats, which also demonstrate age-related cognitive decline, show an increase in PKA phosphorylation of tau at serine 214, a key early event in tau hyperphosphorylation and aggregation. Additionally, we have discovered a decrease in phosphodiesterase levels, which are important regulators the cAMP-PKA pathway. These results mirror changes observed both in humans and the aged rhesus macaque.3,4 This evidence leads us to believe that the aged rat may provide a novel model to study the molecular mechanisms of age-related cognitive decline as well as early stages of LOAD pathology.
1. Alzheimer's Association. Alzheimer's & Dementia Risk Factors | Alzheimer's Association. www.alz.org Available at: https://www.alz.org/alzheimers_disease_causes_risk_factors.asp. (Accessed: 7th February 2018)
2. Paspalas, C. D. et al. The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology. Alzheimers Dement. (2017). doi:10.1016/j.jalz.2017.11.005
3. Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883-891 (2004).
4. Carlyle, B. C. et al. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc. Natl. Acad. Sci. 111, 5036-5041 (2014).