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A rapid gene delivery-based mouse model for early-stage Alzheimer disease-type tauopathy.

Siman R, Lin YG, Malthankar-Phatak G, Dong Y - J. Neuropathol. Exp. Neurol. (2013)

Bottom Line: However, perforant pathway function has not been assessed in experimental models of AD, and a therapeutic agent that protects its structure and function has not yet been identified.Expression of pathologic human tau but not enhanced green fluorescent protein led to specific dose-dependent apoptotic death of perforant pathway neurons and loss of synapses in as little as 2 weeks.This novel adeno-associated virus-based method elicits rapid tauopathy and tau-mediated neurodegeneration localized to the mouse perforant pathway and represents a new experimental approach for studying tau-driven pathogenic processes and tau-based treatment strategies in a highly vulnerable neural circuit.

View Article: PubMed Central - PubMed

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

ABSTRACT
The perforant pathway projection from the entorhinal cortex (EC) to the hippocampal dentate gyrus is critically important for long-term memory and develops tau and amyloid pathologies and progressive degeneration starting in the early stages of Alzheimer disease (AD). However, perforant pathway function has not been assessed in experimental models of AD, and a therapeutic agent that protects its structure and function has not yet been identified. Therefore, we developed a new adeno-associated virus-based mouse model for perforant pathway tauopathy. Microinjection into the lateral EC of vectors designed to express either human tau bearing a pathogenic P301L mutation or enhanced green fluorescent protein as a control selectively drove transgene expression in lateral EC layer II perikarya and along the entire rostrocaudal extent of the lateral perforant pathway afferents and dentate terminal field. After human tau expression, hyperphosphorylated tau accumulated only within EC layer II perikarya, thereby modeling Braak stage I of transentorhinal AD tauopathy. Expression of pathologic human tau but not enhanced green fluorescent protein led to specific dose-dependent apoptotic death of perforant pathway neurons and loss of synapses in as little as 2 weeks. This novel adeno-associated virus-based method elicits rapid tauopathy and tau-mediated neurodegeneration localized to the mouse perforant pathway and represents a new experimental approach for studying tau-driven pathogenic processes and tau-based treatment strategies in a highly vulnerable neural circuit.

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Human tau expression expands over time through polysynaptic afferent pathways. (A) At 3 weeks after intraentorhinal delivery of 1.5 × 109 particles of the AAV-tau vector, human tau expression in the hippocampal formation detected with HT7 staining is confined to the perforant pathway afferents in the stratum lacunosum-moleculare (SLM) and the lateral perforant pathway synaptic field in the dentate outer molecular layer (OML). (B) By 10 weeks, human tau expression expands to include a subset of the granule neuron perforant pathway targets (GCL), the granule neuron mossy fiber projection (MF), and sparse numbers of mossy fiber target neurons in the pyramidal cell layer of the CA3 region (CA3). (C) Higher-power view of HT7-positive human tau expression in the mossy fiber axons and boutons in stratum lucidum of the CA3 sector (SL) and the occasional pyramidal cell neuron (SP, arrow) 14 weeks after intraentorhinal delivery of pathologic human tau. Scale bars = (A) 120 μm; (B) 150 μm; (C) 75 μm.
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Figure 7: Human tau expression expands over time through polysynaptic afferent pathways. (A) At 3 weeks after intraentorhinal delivery of 1.5 × 109 particles of the AAV-tau vector, human tau expression in the hippocampal formation detected with HT7 staining is confined to the perforant pathway afferents in the stratum lacunosum-moleculare (SLM) and the lateral perforant pathway synaptic field in the dentate outer molecular layer (OML). (B) By 10 weeks, human tau expression expands to include a subset of the granule neuron perforant pathway targets (GCL), the granule neuron mossy fiber projection (MF), and sparse numbers of mossy fiber target neurons in the pyramidal cell layer of the CA3 region (CA3). (C) Higher-power view of HT7-positive human tau expression in the mossy fiber axons and boutons in stratum lucidum of the CA3 sector (SL) and the occasional pyramidal cell neuron (SP, arrow) 14 weeks after intraentorhinal delivery of pathologic human tau. Scale bars = (A) 120 μm; (B) 150 μm; (C) 75 μm.

Mentions: Recent evidence from in vitro and in vivo studies indicates that tau is released from neurons and taken up by neighboring ones and can transfer between synaptically interconnected neurons, where it may promote the spread of tauopathy via templated misfolding (6, 7, 49). To investigate whether human tau spreads from the entorhinal cortex via the lateral perforant pathway afferents in the AAV mouse model, we searched for human tau expression in the dorsal hippocampus various times after tau gene delivery to the lateral EC. At the 3-week time point, human tau in the dorsal hippocampal formation was confined to the perforant pathway projection in stratum lacunosum-moleculare and terminal field in OML (Figs. 3, 7). By 10 to 14 weeks, however, human tau expression expanded to include dentate granule neurons, which are the targets for the perforant pathway, the granule neuron axons and boutons comprising the mossy fiber pathway in stratum lucidum, and a small number of mossy fiber target neurons in stratum pyramidale in the CA3 region (Fig. 7). On the other hand, during a 14-week period, there was no evidence for spread of hyperphosphorylated tau, as tau phosphorylated on serine 202 and 205 or threonine 231 remained restricted to surviving neurons in the superficial EC (data not shown). Polysynaptic spread of protein to perforant pathway targets was not observed at comparable or even higher doses of the AAV-eGFP vector (data not shown).


A rapid gene delivery-based mouse model for early-stage Alzheimer disease-type tauopathy.

Siman R, Lin YG, Malthankar-Phatak G, Dong Y - J. Neuropathol. Exp. Neurol. (2013)

Human tau expression expands over time through polysynaptic afferent pathways. (A) At 3 weeks after intraentorhinal delivery of 1.5 × 109 particles of the AAV-tau vector, human tau expression in the hippocampal formation detected with HT7 staining is confined to the perforant pathway afferents in the stratum lacunosum-moleculare (SLM) and the lateral perforant pathway synaptic field in the dentate outer molecular layer (OML). (B) By 10 weeks, human tau expression expands to include a subset of the granule neuron perforant pathway targets (GCL), the granule neuron mossy fiber projection (MF), and sparse numbers of mossy fiber target neurons in the pyramidal cell layer of the CA3 region (CA3). (C) Higher-power view of HT7-positive human tau expression in the mossy fiber axons and boutons in stratum lucidum of the CA3 sector (SL) and the occasional pyramidal cell neuron (SP, arrow) 14 weeks after intraentorhinal delivery of pathologic human tau. Scale bars = (A) 120 μm; (B) 150 μm; (C) 75 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815088&req=5

Figure 7: Human tau expression expands over time through polysynaptic afferent pathways. (A) At 3 weeks after intraentorhinal delivery of 1.5 × 109 particles of the AAV-tau vector, human tau expression in the hippocampal formation detected with HT7 staining is confined to the perforant pathway afferents in the stratum lacunosum-moleculare (SLM) and the lateral perforant pathway synaptic field in the dentate outer molecular layer (OML). (B) By 10 weeks, human tau expression expands to include a subset of the granule neuron perforant pathway targets (GCL), the granule neuron mossy fiber projection (MF), and sparse numbers of mossy fiber target neurons in the pyramidal cell layer of the CA3 region (CA3). (C) Higher-power view of HT7-positive human tau expression in the mossy fiber axons and boutons in stratum lucidum of the CA3 sector (SL) and the occasional pyramidal cell neuron (SP, arrow) 14 weeks after intraentorhinal delivery of pathologic human tau. Scale bars = (A) 120 μm; (B) 150 μm; (C) 75 μm.
Mentions: Recent evidence from in vitro and in vivo studies indicates that tau is released from neurons and taken up by neighboring ones and can transfer between synaptically interconnected neurons, where it may promote the spread of tauopathy via templated misfolding (6, 7, 49). To investigate whether human tau spreads from the entorhinal cortex via the lateral perforant pathway afferents in the AAV mouse model, we searched for human tau expression in the dorsal hippocampus various times after tau gene delivery to the lateral EC. At the 3-week time point, human tau in the dorsal hippocampal formation was confined to the perforant pathway projection in stratum lacunosum-moleculare and terminal field in OML (Figs. 3, 7). By 10 to 14 weeks, however, human tau expression expanded to include dentate granule neurons, which are the targets for the perforant pathway, the granule neuron axons and boutons comprising the mossy fiber pathway in stratum lucidum, and a small number of mossy fiber target neurons in stratum pyramidale in the CA3 region (Fig. 7). On the other hand, during a 14-week period, there was no evidence for spread of hyperphosphorylated tau, as tau phosphorylated on serine 202 and 205 or threonine 231 remained restricted to surviving neurons in the superficial EC (data not shown). Polysynaptic spread of protein to perforant pathway targets was not observed at comparable or even higher doses of the AAV-eGFP vector (data not shown).

Bottom Line: However, perforant pathway function has not been assessed in experimental models of AD, and a therapeutic agent that protects its structure and function has not yet been identified.Expression of pathologic human tau but not enhanced green fluorescent protein led to specific dose-dependent apoptotic death of perforant pathway neurons and loss of synapses in as little as 2 weeks.This novel adeno-associated virus-based method elicits rapid tauopathy and tau-mediated neurodegeneration localized to the mouse perforant pathway and represents a new experimental approach for studying tau-driven pathogenic processes and tau-based treatment strategies in a highly vulnerable neural circuit.

View Article: PubMed Central - PubMed

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

ABSTRACT
The perforant pathway projection from the entorhinal cortex (EC) to the hippocampal dentate gyrus is critically important for long-term memory and develops tau and amyloid pathologies and progressive degeneration starting in the early stages of Alzheimer disease (AD). However, perforant pathway function has not been assessed in experimental models of AD, and a therapeutic agent that protects its structure and function has not yet been identified. Therefore, we developed a new adeno-associated virus-based mouse model for perforant pathway tauopathy. Microinjection into the lateral EC of vectors designed to express either human tau bearing a pathogenic P301L mutation or enhanced green fluorescent protein as a control selectively drove transgene expression in lateral EC layer II perikarya and along the entire rostrocaudal extent of the lateral perforant pathway afferents and dentate terminal field. After human tau expression, hyperphosphorylated tau accumulated only within EC layer II perikarya, thereby modeling Braak stage I of transentorhinal AD tauopathy. Expression of pathologic human tau but not enhanced green fluorescent protein led to specific dose-dependent apoptotic death of perforant pathway neurons and loss of synapses in as little as 2 weeks. This novel adeno-associated virus-based method elicits rapid tauopathy and tau-mediated neurodegeneration localized to the mouse perforant pathway and represents a new experimental approach for studying tau-driven pathogenic processes and tau-based treatment strategies in a highly vulnerable neural circuit.

Show MeSH
Related in: MedlinePlus