Accumulated Tau Protein Expressed In MEC Induces Reduction Of Neuronal Activity And Cognitive Deficits

One of the essential characteristic pathological changes in Alzheimer’s disease (AD) was that abnormal microtubule-associated Tau formed neurofibrillary tangles selectively in the different types of neurons. According to the Braak stage, the entorhinal cortex was the first brain region that affected abnormal Tau protein, meanwhile, some imaging studies shown that decreased neuronal activity was also consistent with the Braak stage. In order to explore the impact of abnormal Tau proteins on neuronal activity, we expressed P301LTau or overexpressed human Tau40proteins in the entorhinal cortex to simulate the early stage of AD patients. We found that P301LTau protein expressed in MEC for a month caused cognitive impairments in mice, whereas overexpressed Tau40in MEC for a month did not give rise to cognitive impairment in mice. P301LTau protein expressed in MEC for a month led hyperphosphorylation of Tau protein, decreased of synaptic plasticity and neuronal activity. Tau40overexpressed in MEC for1month inhibited neuronal activity. Tau40overexpressed in MEC for three or six months caused olfactory dependent memory decline, but spatial memory was not damaged. Tau protein propagated to hippocampus when Tau40overexpressed in MEC for3months. Recent studies have reported a correlation between dementia and low blood pressure. How hypotension is associated with the increased risk of Alzheimer disease (AD) remains unclear. Here we show that one month treatment of losartan, an angiotensin II type1(AT1) receptor, causes chronic and sustained hypotension, along with oxidative stress in adult male Sprague-Dawley rats. Furthermore, we show that losartan treatment increases the level of inactivated protein phosphotase2A (PP2A) and the hyperphosphorylation of Tau at Ser199and Ser396. Rats treated with losartan present memory deficits and decreases of spine-density. These findings suggest that losartan-induced hypotension may increase the risk of AD like pathological alteration and behavioral impairment through oxidative stress which leads to tau hyperphosphorylation and loss of spine. Alzheimer’s disease (AD) is a common neurodegenerative disorder. The vast majority of AD cases suffer the late-onset, largely’sporadic’ form of the disease. Because many data suggest that environmental factors may play a role in the development of late-onset AD, it is important to investigate how environmental factors impact on and contribute to the pathogenesis of the disease. Currently, the impact of social isolation (SI) on wild-type mice cognitive function is not clear. Whether SI changes adrenergic signaling pathway and the relationship between SI and the pathogenesis of AD is unclear. In order to study these issues,3-week-old weaned mice were fed for six weeks social isolated. We found that SI mice exhibited cue-dependent fear test decline and anxiety, which were depended on amygdala. Moreover, spatial learning ability of SI mice was impaired, which was depended on hippocampus. The adrenergic signaling pathway and APP amyloidogenic pathway that increased productions of Aβ40and Aβ42in SI mice were activated. SI mice synaptic plasticity was also inhibited. Cognition of SI mice fed with β-receptor antagonist Propranolol was improve.