Abstract
Alzheimer’s disease (AD) and cerebral ischemia (CI) are neuropathologies that are characterized by aggregates of tau protein, a hallmark of cognitive disorder and dementia. Protein accumulation can be induced by autophagic failure. Autophagy is a metabolic pathway involved in the homeostatic recycling of cellular components. However, the role of autophagy in those tauopathies remains unclear. In this study, we performed a comparative analysis to identify autophagy related markers in tauopathy generated by AD and CI during short-term, intermediate, and long-term progression using the 3xTg-AD mouse model (aged 6,12, and 18 months) and the global CI 2-VO (2-Vessel Occlusion) rat model (1,15, and 30 days post-ischemia). Our findings confirmed neuronal loss and hyperphosphorylated tau aggregation in the somatosensory cortex (SS-Cx) of the 3xTg-AD mice in the late stage (aged 18 months), which was supported by a failure in autophagy. These results were in contrast to those obtained in the SS-Cx of the CI rats, in which we detected neuronal loss and tauopathy at 1 and 15 days post-ischemia, and this phenomenon was reversed at 30 days. We proposed that this phenomenon was associated with autophagy induction in the late stage, since the data showed a decrease in p-mTOR activity, an association of Beclin-1 and Vps34, a progressive reduction in PHF-1, an increase in LC3B puncta and autophago-lysosomes formation were observed. Furthermore, the survival pathways remained unaffected. Together, our comparative study suggest that autophagy could ameliorates tauopathy in CI but not in AD, suggesting a differential temporal approach to the induction of neuroprotection and the prevention of neurodegeneration.
Highlights
Cerebral ischemia (CI) is considered the third leading cause of death worldwide (Wen et al, 2004; Zheng et al, 2010), contributing to the development of cognitive decline and dementia, which is induced by a sedentary lifestyle, unhealthy eating habits, diabetes, and other metabolic diseases (Boerma, 2011)
Comparative Analysis of Neuronal Loss in the Primary Somatosensory Cortex of 3xTg-Alzheimer’s disease (AD) Mice and Global Cerebral Ischemic Rats Neuronal loss is a major neuropathological indicator used to measure the degree of alteration in nervous tissue (Buchman et al, 2013) and has been previously demonstrated in both AD and cerebral ischemia (CI) (Cespedes-Rubio et al, 2010; Abuhassan et al, 2011)
In the global CI rat model, the penumbral area in the somatosensory cortex, which is closest to the focus in the region of the middle cerebral artery, demonstrated a significant reduction in the nuclei immunoreactivity (NeuN) immunoreactivity (Figure 1B) at day 1 (2,322 ± 109 nuclei) and day 15 (2,531 ± 185 nuclei) post-ischemia compared with the control rats (2,780 ± 158 and 3,395 ± 206, respectively)
Summary
Cerebral ischemia (CI) is considered the third leading cause of death worldwide (Wen et al, 2004; Zheng et al, 2010), contributing to the development of cognitive decline and dementia, which is induced by a sedentary lifestyle, unhealthy eating habits, diabetes, and other metabolic diseases (Boerma, 2011) It is characterized by an occlusion of the cerebral artery, which results in the deprivation of trophic factors and metabolic substrates, decreased blood flow, and the activation of cell death pathways (Roberts et al, 2013). Excitotoxicity in CI alters the cellular balance (Arundine and Tymianski, 2004), inducing tau hyperphosphorylation in early- and intermediate-stage post-ischemia (Wen et al, 2004; Cespedes-Rubio et al, 2010) This process is associated with a high incidence of cognitive disorder after stroke (Zheng et al, 2010; Castro-Alvarez et al, 2011). The rapid dephosphorylation of tau occurs, and after blood reperfusion, there is evidence of slow but steady hyperphosphorylation, which causes an accumulation of the tau protein, resulting in long-term brain damage (Wen et al, 2004)
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