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The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.

Siman R, Cocca R, Dong Y - PLoS ONE (2015)

Bottom Line: It did not alter human tau mRNA or total protein levels.These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis.The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Center for Brain Injury and Repair, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT
The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer's disease (AD) that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis. The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.

No MeSH data available.


Related in: MedlinePlus

Rapamycin inhibits pathological tau-activated innate immunity in the lateral perforant pathway synaptic field.Microglial-mediated innate immunity in response to pathological tau-induced neurodegeneration was evaluated by immunohistochemical labeling for mouse IgG. (A) Cells with modest IgG expression were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expressing pathological human tau in the lateral perforant pathway in mice treated with vehicle, a dense band of microglia with increased IgG expression was observed in the dentate gyrus outer molecular layer. (C) The morphology of IgG-expressing cells confirmed their identification as microglia. Whereas chronic rapamycin treatment modestly reduced microglial IgG expression in the contralateral hemisphere (D), it markedly attenuated the reactive microgliosis-associated increase in IgG expression in the lateral perforant pathway synaptic field (E, low magnification; F, high magnification). Essentially identical findings were made in the infrapyramidal blade of the dentate gyrus. Scale bar = 20 μm (A,B,D,E), 10 μm (C,F).
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pone.0142340.g007: Rapamycin inhibits pathological tau-activated innate immunity in the lateral perforant pathway synaptic field.Microglial-mediated innate immunity in response to pathological tau-induced neurodegeneration was evaluated by immunohistochemical labeling for mouse IgG. (A) Cells with modest IgG expression were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expressing pathological human tau in the lateral perforant pathway in mice treated with vehicle, a dense band of microglia with increased IgG expression was observed in the dentate gyrus outer molecular layer. (C) The morphology of IgG-expressing cells confirmed their identification as microglia. Whereas chronic rapamycin treatment modestly reduced microglial IgG expression in the contralateral hemisphere (D), it markedly attenuated the reactive microgliosis-associated increase in IgG expression in the lateral perforant pathway synaptic field (E, low magnification; F, high magnification). Essentially identical findings were made in the infrapyramidal blade of the dentate gyrus. Scale bar = 20 μm (A,B,D,E), 10 μm (C,F).

Mentions: A subpopulation of microglia engages in antigen presentation and innate immune surveillance, and is identifiable by surface immunoglobulin G (IgG) expression [44]. We investigated the effect of tau-induced lesions of the lateral perforant pathway on microglial IgG expression and examined the influence of chronic rapamycin on tau-mediated activation of innate immunity. As shown in Fig 7A, IgG was expressed by scattered cells in dentate gyrus with short, thin, highly ramified processes characteristic of microglial morphology. Chronic rapamycin treatment lowered microglial IgG expression in the dentate gyrus (Fig 7D) and throughout the control hemisphere, consistent with its powerful immunosuppressant activity. At 3 weeks after expression of pathological human tau in the lateral perforant pathway, a band of microglia with increased IgG expression appeared in the denervated dentate OML (Fig 7B and 7C). Chronic rapamycin partially blocked the tau-induced increase in microglial IgG expression in the lateral perforant pathway terminal field (Fig 7E and 7F). Thus, rapamycin protected not only tau-mediated loss of lateral perforant pathway synapses as evidenced from presynaptic terminal zinc staining, but also inhibited the reactive microgliosis and activation of innate neuroimmunity that are triggered by the synaptic degeneration.


The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.

Siman R, Cocca R, Dong Y - PLoS ONE (2015)

Rapamycin inhibits pathological tau-activated innate immunity in the lateral perforant pathway synaptic field.Microglial-mediated innate immunity in response to pathological tau-induced neurodegeneration was evaluated by immunohistochemical labeling for mouse IgG. (A) Cells with modest IgG expression were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expressing pathological human tau in the lateral perforant pathway in mice treated with vehicle, a dense band of microglia with increased IgG expression was observed in the dentate gyrus outer molecular layer. (C) The morphology of IgG-expressing cells confirmed their identification as microglia. Whereas chronic rapamycin treatment modestly reduced microglial IgG expression in the contralateral hemisphere (D), it markedly attenuated the reactive microgliosis-associated increase in IgG expression in the lateral perforant pathway synaptic field (E, low magnification; F, high magnification). Essentially identical findings were made in the infrapyramidal blade of the dentate gyrus. Scale bar = 20 μm (A,B,D,E), 10 μm (C,F).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4634963&req=5

pone.0142340.g007: Rapamycin inhibits pathological tau-activated innate immunity in the lateral perforant pathway synaptic field.Microglial-mediated innate immunity in response to pathological tau-induced neurodegeneration was evaluated by immunohistochemical labeling for mouse IgG. (A) Cells with modest IgG expression were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expressing pathological human tau in the lateral perforant pathway in mice treated with vehicle, a dense band of microglia with increased IgG expression was observed in the dentate gyrus outer molecular layer. (C) The morphology of IgG-expressing cells confirmed their identification as microglia. Whereas chronic rapamycin treatment modestly reduced microglial IgG expression in the contralateral hemisphere (D), it markedly attenuated the reactive microgliosis-associated increase in IgG expression in the lateral perforant pathway synaptic field (E, low magnification; F, high magnification). Essentially identical findings were made in the infrapyramidal blade of the dentate gyrus. Scale bar = 20 μm (A,B,D,E), 10 μm (C,F).
Mentions: A subpopulation of microglia engages in antigen presentation and innate immune surveillance, and is identifiable by surface immunoglobulin G (IgG) expression [44]. We investigated the effect of tau-induced lesions of the lateral perforant pathway on microglial IgG expression and examined the influence of chronic rapamycin on tau-mediated activation of innate immunity. As shown in Fig 7A, IgG was expressed by scattered cells in dentate gyrus with short, thin, highly ramified processes characteristic of microglial morphology. Chronic rapamycin treatment lowered microglial IgG expression in the dentate gyrus (Fig 7D) and throughout the control hemisphere, consistent with its powerful immunosuppressant activity. At 3 weeks after expression of pathological human tau in the lateral perforant pathway, a band of microglia with increased IgG expression appeared in the denervated dentate OML (Fig 7B and 7C). Chronic rapamycin partially blocked the tau-induced increase in microglial IgG expression in the lateral perforant pathway terminal field (Fig 7E and 7F). Thus, rapamycin protected not only tau-mediated loss of lateral perforant pathway synapses as evidenced from presynaptic terminal zinc staining, but also inhibited the reactive microgliosis and activation of innate neuroimmunity that are triggered by the synaptic degeneration.

Bottom Line: It did not alter human tau mRNA or total protein levels.These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis.The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Center for Brain Injury and Repair, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT
The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer's disease (AD) that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis. The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.

No MeSH data available.


Related in: MedlinePlus