Premium
[P4–098]: IMPACT OF CHRONIC STRESS ON TAU PHOSPHORYLATION IN THE HIPPOCAMPUS OF FEMALE RATS IN DIFFERENT REPRODUCTIVE STAGES
Author(s) -
Muñoz Daniel Eduardo
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1963
Subject(s) - hippocampus , chronic stress , western blot , medicine , endocrinology , immunohistochemistry , physiology , biology , biochemistry , gene
Background:The microtubule-associated protein tau is spliced by variable RNA to produce six different isoforms and is divided into two classes according to the number of C-terminal repeats, designated as three repeats (3R) tau and four repeats (4R) Tau. The accumulation of individual isoforms of 3R-tau or 4R-tau, or the imbalance ratio of 3R / 4R may be a risk factor for neurodegenerative diseases including Alzheimer’s disease (AD), but is still lacking in research. In addition, the effects of 3R-tau and 4R-tau on learning and memory remain unknown, and the molecular mechanisms are poorly understood. Methods: The AAV-tau-0N3R, AAV-tau-1N3R and AAV-tau-2N3R were mixed into equal volume of 3R-tau virus; AAV-tau-0N4R, AAV-tau-1N4R and AAV-tau-2N4R were mixed in equal volumes of 4R-tau virus. Then we injected stereotaxically the mixed 3R-, 4R-tau or the vector into the dorsal hippocampus CA3 of 2-mo-old C57BL/6 mice. One month after viral expression, we used Morris water maze (MWM) and fear condition to evaluate the spatial learning and memory. Then we used LTP for detecting the synaptic connections from CA3 to CA1, Golgi Staining the number of dendritic spines, western blot and immunohistochemistry to show learning and memory relate proteins and DNA damaged markergH2A.X levels. We measured the level of SOD, MDA, GSH–P to test oxidative stress. Results:Here we found that over-expression of 3R-tau induced learning and memory deficits with impairments of synaptic plasticity. Both in vivo and in vitro data demonstrated that over-expression of 3R-tau caused remarkable DNA double-strand breaks (DSBs), accompanied by increased malondialdehyde (MDA) with decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). We identified oxidative stress and subsequent DNA damage as a mechanical link between 3R-tau aggregation and neuron dysfunction, leading to impairment of learning and memory. Notably, this effect was reversed after the administration of the antioxidant vitamin E or vitamin C. Conclusions:Over-expression of 3R-tau leads to synaptic defects and memory impairment by oxidative stress-mediated DNA double strand breaks. Notably, this effect was reversed after the administration of the antioxidant vitamin E or vitamin C.