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Characterization of a new animal model of Alzheimer's disease: relevance of Tau phosphorylation in hippocampal interneurons

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Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia

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[eng] The neuropathological hallmarks of Alzheimer’s disease are senile plaques, extracellular deposits of amyloid-β peptide (Aβ), and neurofibrillary tangles, intracellular aggregates of hyperphosphorylated Tau protein (P-Tau). At the functional level, Alzheimer’s disease involves synaptic dysfunction, aberrant network activity, and cognitive impairment, eventually resulting in dementia. Remarkably, individuals presenting Aβ and P-Tau without cognitive impairment have been reported. This cognitive resilience to Alzheimer’s disease is believed to involve synaptic preservation.

In Alzheimer’s disease, Aβ and P-Tau exert toxicity either independently or synergistically. However, Tau is pivotal in mediating the synaptotoxicity induced by Aβ, neurodegeneration, and cognitive decline. Tau is a canonical microtubule-binding protein. Nevertheless, its physiological roles are currently recognized to extend far beyond microtubule stabilization, including participation in synaptic plasticity and DNA protection. Although the regulation of Tau function depends on phosphorylation, the association of P-Tau with Alzheimer’s disease and other tauopathies has established the notion that it is invariably pathological.

Aberrant network activity, hyperexcitability, and altered oscillatory activity, which indicate an imbalance between excitation and inhibition in neural circuits, have been described in Alzheimer’s disease. Hence, dysfunction of the GABAergic system has been suggested to underlie network abnormalities. Studies from our group have revealed synaptic alterations in the GABAergic septohippocampal pathway and its implication in the emergence of abnormal hippocampal oscillatory activity in J20 and VLW animals, Alzheimer’s disease mouse models that accumulate Aβ and P-Tau, respectively. GABAergic neurons in the medial septum control GABAergic hippocampal interneurons, which govern principal cell activity, hence modulating hippocampal oscillations.

Given the myriad of physiological roles of Tau and the impact of phosphorylation on its activity, we have studied its phosphorylation pattern in physiological and pathological conditions in mice and human subjects. Our data show that control mice and human subjects present Tau phosphorylated at Thr205 and Ser262 in the soma of hippocampal interneurons, pointing to a physiological role of these P-Tau species in this neuron population. Moreover, we have observed these P-Tau species in the soma of hippocampal interneurons in Alzheimer’s disease patients and in J20 and VLW mice. The presence of Tau phosphorylated at Thr205 correlates with the Aβ plaque burden in J20 animals, suggesting an inductive effect of Aβ on Tau phosphorylation at this site. Conversely, the accumulation of Tau phosphorylated at Ser262 is unchanged in pathological conditions, implying a physiological role of this P-Tau. In addition, our data indicate that
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the presence of mutant human Tau in pyramidal neurons in VLW mice induces the phosphorylation of endogenous murine Tau at Thr231 in hippocampal interneurons.

Furthermore, to recapitulate the complete spectrum of Alzheimer’s disease pathology, we have crossed J20 and VLW mice. In the resulting J20/VLW animals, which simultaneously present Aβ and P-Tau, our findings reveal no differences in Aβ burden or P-Tau levels compared to single transgenic mice. However, J20/VLW animals present a distinct Tau phosphorylation pattern in hippocampal interneurons. Our data show that GABAergic septohippocampal innervation is dramatically altered in J20 and VLW animals, whereas it is preserved in J20/VLW mice. Moreover, we have found that hippocampal oscillations are partially conserved in J20/VLW animals, in contrast to single transgenic mice. Finally, J20/VLW mice display preserved cognitive function, contrary to J20 and VLW animals.

Taken together, our findings point to a physiological role of Tau phosphorylation in the somatodendritic compartment of hippocampal interneurons. Moreover, they suggest that a particular Tau phosphorylation signature in this neuron population protects against the loss of GABAergic septohippocampal innervation, thereby avoiding alterations in hippocampal oscillatory activity and, thus, preventing cognitive impairment in J20/VLW mice. Lastly, these data highlight J20/VLW mice as a suitable animal model to explore the cognitive resilience to Alzheimer’s disease.

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Tesis Doctorals - Departament - Biologia Cel·lular, Fisiologia i Immunologia

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Characterization of a new animal model of Alzheimer's disease: relevance of Tau phosphorylation in hippocampal interneurons