Abstract
Microtubule-associated protein tau aggregates constitute the characteristic neuropathological features of several neurodegenerative diseases grouped under the name of tauopathies. It is now clear that the process of tau aggregation is associated with neurodegeneration. Several transgenic tau mouse models have been developed where tau progressively aggregates, causing neuronal death. Previously we have shown that transplantation of astrocytes in P301S tau transgenic mice rescues cortical neuron death, implying that the endogenous astrocytes are deficient in survival support. We now show that the gliosis markers Glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100β) are elevated in brains from P301S tau mice compared to control C57Bl/6 mice whereas the expression of proteins involved in glutamine/glutamate metabolism are reduced, pointing to a functional deficit. To test whether astrocytes from P301S mice are intrinsically deficient, we co-cultured astrocytes and neurons from control and P301S mice. Significantly more C57-derived and P301S-derived neurons survived when cells were cultured with C57-derived astrocytes or astrocyte conditioned medium (C57ACM) than with P301S-derived astrocytes or astrocyte conditioned medium (P301SACM), or ACM from P301L tau mice, where the transgene is also specifically expressed in neurons. The astrocytic alterations developed in mice during the first postnatal week of life. In addition, P301SACM significantly decreased presynaptic (synaptophysin, SNP) and postsynaptic (postsynaptic density protein 95, PSD95) protein expression in cortical neuron cultures whereas C57ACM enhanced these markers. Since thrombospondin 1 (TSP-1) is a major survival and synaptogenic factor, we examined whether TSP-1 is deficient in P301S mouse brains and ACM. Significantly less TSP-1 was expressed in the brains of P301S tau mice or produced by P301S-derived astrocytes, whereas supplementation of P301SACM with TSP-1 increased its neurosupportive capacity. Our results demonstrate that P301S-derived astrocytes acquire an early functional deficiency that may explain in part the loss of cortical neurons in the P301S tau mice.
Highlights
Several neurodegenerative diseases, such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), argyrophilic grain disease, and inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) are characterized by the presence of Sidoryk-Wegrzynowicz et al Acta Neuropathologica Communications (2017) 5:89Despite the knowledge that the presence of misfolded hyperphosphorylated tau is critical for development of disease and neuronal death [15, 36], the mechanism of tau-related toxicity is still not clear
Counting the number of neurons after 4 or 8 days using anti-β-III-tubulin, and astrocytes using anti-Glial fibrillary acidic protein (GFAP), showed that there were significantly higher numbers of neurons cultured from C57 mice (C57N) or P301S tau mice (P301SN) when cells were cocultured with C57A than with P301SA, especially notable after 8 days in culture (Fig. 3b, c)
Similar lack of neuronal support by Astrocyte conditioned medium (ACM) were observed in an independent P301L mouse model, where tau is expressed under the same neuronal specific Thy1 promoter, indicating that our results can be generalized as being a result of tau pathology
Summary
Several neurodegenerative diseases, such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), argyrophilic grain disease, and inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) are characterized by the presence of Sidoryk-Wegrzynowicz et al Acta Neuropathologica Communications (2017) 5:89Despite the knowledge that the presence of misfolded hyperphosphorylated tau is critical for development of disease and neuronal death [15, 36], the mechanism of tau-related toxicity is still not clear. Tau pathology develops stereotypically between 2 and 5 months of age culminating in neuronal death most notably observed in the superficial layers of the motor and, perirhinal and piriform cortices [1, 9, 51, 52]. To determine whether altering the environment can extend neuronal survival, we transplanted neuron precursor cell (NPC)-derived astrocytes and showed that neuronal death in the superficial layers of the motor cortex was prevented [19], indicating a deficiency in survival support, or a gain of toxic functions, by the endogenous astrocytes. We investigate the reasons why astrocytes from P301S mice do not prevent neuronal death whereas transplanted control astrocytes do. We show that astrocytes derived from the superficial cortex of P301S mice exhibit changes in cell specific markers that indicate astrocyte dysfunction. We demonstrate in in vitro systems that astrocytes or astrocyte conditioned medium from wild type mice have neuroprotective and synaptogenic functions that are absent in astrocytes from P301S- or P301L-tau expressing mice, which can be attributed in part to a reduction in thrombospondin-1 (TSP-1) expression in conditioned medium from P301S astrocytes
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