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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

Dose-dependent tau neurotoxicity for lateral perforant pathway neurons is tied to trans-synaptic expansion of human tau expression, and both are reduced by rapamycin.Left column–NeuN immunohistochemistry in the lateral entorhinal cortex 5 weeks after AAV-based human tau gene delivery. Right column–Total human tau immunohistochemistry in the ipsilateral dentate gyrus. A) After delivery of 0.5 billion particles of AAV-hTauP301L (low dose), there is no appreciable neuronal loss in the lateral entorhinal layer II (see also Siman et al., 2013). In the dentate gyrus under these conditions, human tau is confined to the terminal field for the lateral perforant pathway in the outer molecular layer (OML). Additional abbreviations: MML- middle molecular layer; IML- inner molecular layer; GCL- granule cell layer. B) After delivery of 1.5 billion particles of AAV-hTauP301L (high dose), there is extensive loss of lateral entorhinal layer II neurons. In the dentate gyrus, human tau is present not only in the lateral perforant pathway terminal field in the OML, but also in scattered granule neurons in the GCL. C) Chronic treatment with vehicle does not appreciably alter the toxicity of pathological human tau for the layer II neurons of lateral entorhinal cortex or the spread of human tau expression to some of the dentate granule neurons. D) Chronic rapamycin treatment partially protects the perforant pathway layer II neurons from tau-mediated degeneration, and also partially inhibits the trans-synaptic spread of human tau expression to their granule neuron targets. Scale bar (left) = 200 μm; Scale bar (right) = 40 μm (A,B), 20 μm (C,D).
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pone.0142340.g003: Dose-dependent tau neurotoxicity for lateral perforant pathway neurons is tied to trans-synaptic expansion of human tau expression, and both are reduced by rapamycin.Left column–NeuN immunohistochemistry in the lateral entorhinal cortex 5 weeks after AAV-based human tau gene delivery. Right column–Total human tau immunohistochemistry in the ipsilateral dentate gyrus. A) After delivery of 0.5 billion particles of AAV-hTauP301L (low dose), there is no appreciable neuronal loss in the lateral entorhinal layer II (see also Siman et al., 2013). In the dentate gyrus under these conditions, human tau is confined to the terminal field for the lateral perforant pathway in the outer molecular layer (OML). Additional abbreviations: MML- middle molecular layer; IML- inner molecular layer; GCL- granule cell layer. B) After delivery of 1.5 billion particles of AAV-hTauP301L (high dose), there is extensive loss of lateral entorhinal layer II neurons. In the dentate gyrus, human tau is present not only in the lateral perforant pathway terminal field in the OML, but also in scattered granule neurons in the GCL. C) Chronic treatment with vehicle does not appreciably alter the toxicity of pathological human tau for the layer II neurons of lateral entorhinal cortex or the spread of human tau expression to some of the dentate granule neurons. D) Chronic rapamycin treatment partially protects the perforant pathway layer II neurons from tau-mediated degeneration, and also partially inhibits the trans-synaptic spread of human tau expression to their granule neuron targets. Scale bar (left) = 200 μm; Scale bar (right) = 40 μm (A,B), 20 μm (C,D).

Mentions: In our AAV model of early-stage AD-type tauopathy, human tau expression initially is confined to the neurons of origin in entorhinal layer II and the perforant pathway axonal projection as it traverses the hippocampal stratum lacunosum-moleculare (SLM), and terminates in the lateral perforant pathwayterminal field in the dentate outer molecular layer (OML). At later times, however, human tau expression spreads to the perforant pathway target neurons, the dentate granule cells, shortly after the pathway has degenerated [32]. Here, we investigated the effect of rapamycin on the trans-synaptic spread of human tau expression. At 5 weeks after delivery of a low dose of AAV-hTauP301L that is not acutely toxic to the perforant pathway (0.5 billion particles; [32]), NeuN staining revealed an intact layer II in the lateral entorhinal cortex (Fig 3A left). In dentate gyrus, human tau was confined to the perforant pathway terminal field in the OML (Fig 3A, right). In contrast, at 5 weeks after delivery of a higher, toxic dose of the tau vector (1.5 billion particles), lateral entorhinal layer II was depleted of surviving neurons (Fig 3B left), and in the dentate gyrus human tau expression expanded to include a small minority of granule neurons in the GCL (Fig 3B, right). Whereas chronic treatment with vehicle did not affect the layer II neuronal loss (Fig 3C left) or trans-synaptic spread of human tau expression (Fig 3C, right), rapamycin not only preserved the entorhinal layer II neurons (Fig 3D left) but also reduced the trans-synaptic expansion of human tau (Fig 3D, right). The number of human tau-expressing dentate granule neurons was reduced 43% by chronic rapamycin treatment (Table 1; p = 0.035).


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)

Dose-dependent tau neurotoxicity for lateral perforant pathway neurons is tied to trans-synaptic expansion of human tau expression, and both are reduced by rapamycin.Left column–NeuN immunohistochemistry in the lateral entorhinal cortex 5 weeks after AAV-based human tau gene delivery. Right column–Total human tau immunohistochemistry in the ipsilateral dentate gyrus. A) After delivery of 0.5 billion particles of AAV-hTauP301L (low dose), there is no appreciable neuronal loss in the lateral entorhinal layer II (see also Siman et al., 2013). In the dentate gyrus under these conditions, human tau is confined to the terminal field for the lateral perforant pathway in the outer molecular layer (OML). Additional abbreviations: MML- middle molecular layer; IML- inner molecular layer; GCL- granule cell layer. B) After delivery of 1.5 billion particles of AAV-hTauP301L (high dose), there is extensive loss of lateral entorhinal layer II neurons. In the dentate gyrus, human tau is present not only in the lateral perforant pathway terminal field in the OML, but also in scattered granule neurons in the GCL. C) Chronic treatment with vehicle does not appreciably alter the toxicity of pathological human tau for the layer II neurons of lateral entorhinal cortex or the spread of human tau expression to some of the dentate granule neurons. D) Chronic rapamycin treatment partially protects the perforant pathway layer II neurons from tau-mediated degeneration, and also partially inhibits the trans-synaptic spread of human tau expression to their granule neuron targets. Scale bar (left) = 200 μm; Scale bar (right) = 40 μm (A,B), 20 μm (C,D).
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pone.0142340.g003: Dose-dependent tau neurotoxicity for lateral perforant pathway neurons is tied to trans-synaptic expansion of human tau expression, and both are reduced by rapamycin.Left column–NeuN immunohistochemistry in the lateral entorhinal cortex 5 weeks after AAV-based human tau gene delivery. Right column–Total human tau immunohistochemistry in the ipsilateral dentate gyrus. A) After delivery of 0.5 billion particles of AAV-hTauP301L (low dose), there is no appreciable neuronal loss in the lateral entorhinal layer II (see also Siman et al., 2013). In the dentate gyrus under these conditions, human tau is confined to the terminal field for the lateral perforant pathway in the outer molecular layer (OML). Additional abbreviations: MML- middle molecular layer; IML- inner molecular layer; GCL- granule cell layer. B) After delivery of 1.5 billion particles of AAV-hTauP301L (high dose), there is extensive loss of lateral entorhinal layer II neurons. In the dentate gyrus, human tau is present not only in the lateral perforant pathway terminal field in the OML, but also in scattered granule neurons in the GCL. C) Chronic treatment with vehicle does not appreciably alter the toxicity of pathological human tau for the layer II neurons of lateral entorhinal cortex or the spread of human tau expression to some of the dentate granule neurons. D) Chronic rapamycin treatment partially protects the perforant pathway layer II neurons from tau-mediated degeneration, and also partially inhibits the trans-synaptic spread of human tau expression to their granule neuron targets. Scale bar (left) = 200 μm; Scale bar (right) = 40 μm (A,B), 20 μm (C,D).
Mentions: In our AAV model of early-stage AD-type tauopathy, human tau expression initially is confined to the neurons of origin in entorhinal layer II and the perforant pathway axonal projection as it traverses the hippocampal stratum lacunosum-moleculare (SLM), and terminates in the lateral perforant pathwayterminal field in the dentate outer molecular layer (OML). At later times, however, human tau expression spreads to the perforant pathway target neurons, the dentate granule cells, shortly after the pathway has degenerated [32]. Here, we investigated the effect of rapamycin on the trans-synaptic spread of human tau expression. At 5 weeks after delivery of a low dose of AAV-hTauP301L that is not acutely toxic to the perforant pathway (0.5 billion particles; [32]), NeuN staining revealed an intact layer II in the lateral entorhinal cortex (Fig 3A left). In dentate gyrus, human tau was confined to the perforant pathway terminal field in the OML (Fig 3A, right). In contrast, at 5 weeks after delivery of a higher, toxic dose of the tau vector (1.5 billion particles), lateral entorhinal layer II was depleted of surviving neurons (Fig 3B left), and in the dentate gyrus human tau expression expanded to include a small minority of granule neurons in the GCL (Fig 3B, right). Whereas chronic treatment with vehicle did not affect the layer II neuronal loss (Fig 3C left) or trans-synaptic spread of human tau expression (Fig 3C, right), rapamycin not only preserved the entorhinal layer II neurons (Fig 3D left) but also reduced the trans-synaptic expansion of human tau (Fig 3D, right). The number of human tau-expressing dentate granule neurons was reduced 43% by chronic rapamycin treatment (Table 1; p = 0.035).

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