Abstract
Alzheimer’s disease is pathologically characterized by abnormal accumulation of amyloid-beta plaques, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation, including excessive zinc released by presynaptic neurons, plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimer’s disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of the mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, and synaptic and cognitive impairment has not been fully elucidated in vivo. Here, we assessed the effect of pathological zinc concentrations in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were laterally ventricularly injected with zinc, treated with rapamycin (intraperitoneal injection) for 1 week, and assessed using the Morris water maze. Evaluation of oxidative stress, tau phosphorylation, and synaptic impairment was performed using the hippocampal tissue of the rats by biochemical assays and immunofluorescence staining. The results from the Morris water maze showed that the capacity of spatial memory was impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356 and decreased the levels of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in SH-SY5Y cells and in zinc-treated rats compared with the control groups. Increased expression of reactive oxygen species was observed in zinc sulfate-induced SH-SY5Y cells and in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued zinc-induced increases in mTOR/p70S6K activation, tau phosphorylation, and oxidative stress, and Nrf2/HO-1 inactivation, cognitive impairment, and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress, and synaptic impairment by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO-1 activity.
Highlights
Alzheimer’s disease (AD) is pathologically characterized by abnormal accumulation of amyloid-beta (Ab) plaques, neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, synaptic impairment, and neurodegeneration [1]
We assessed the potential involvement of the mammalian target of rapamycin (mTOR)/P70S6K pathway in zinc sulfate-induced alterations in SH-SY5Y cells and zinc sulfate-injected rats
Zinc sulfate significantly elevated the ratio of phosphorylated mTOR (S2448)/total mTOR by approximately 20% and phosphorylated P70S6K (T389)/total P70S6K in SH-SY5Y cells (p = 0.046 and p = 0.002, respectively) compared to the control group (Figures 1A, B)
Summary
Alzheimer’s disease (AD) is pathologically characterized by abnormal accumulation of amyloid-beta (Ab) plaques, neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, synaptic impairment, and neurodegeneration [1]. The microtubule-associated protein tau is abnormally hyperphosphorylated and mainly aggregates into paired helical filaments (PHFs) in the brains of patients with AD [2, 3]. The mammalian target of rapamycin (mTOR) and ribosomal S6 protein kinase (p70S6K) are serine/threonine kinases that play key roles in the regulation of protein synthesis and degradation, age-dependent cognitive decline, and pathogenesis of AD [6,7,8]. Accumulating evidence has demonstrated that abnormal mTOR signaling in the brain affects several pathways in AD that are associated with metabolism, insulin signaling, protein aggregation, mitochondrial function, and oxidative stress [9]. A well-known inhibitor of mTOR, plays an important role in autophagy and insulin signaling [12, 13] and regulates tau phosphorylation [11, 14, 15]. The upstream or downstream effectors controlled by mTOR that contribute to changes in neuronal functions and cognitive decline have not been fully elucidated
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