Abstract
Phosphatase and tensin homolog (PTEN) regulates synaptic density in development; however, whether PTEN also regulates synapse loss in a neurodegenerative disorder such as frontotemporal lobar degeneration with Tau deposition (FTLD-Tau) has not been explored. Here, we found that pathological Tau promotes early activation of PTEN, which precedes apoptotic caspase-3 cleavage in the rTg4510 mouse model of FTLD-Tau. We further demonstrate increased synaptic and neuronal exposure of the apoptotic signal phosphatidylserine that tags neuronal structures for microglial uptake, thereby linking PTEN activation to synaptic and neuronal structure elimination. By applying pharmacological inhibition of PTEN's protein phosphatase activity, we observed that microglial uptake can be decreased in Tau transgenic mice. Finally, we reveal a dichotomous relationship between PTEN activation and age in FTLD-Tau patients and healthy controls. Together, our findings suggest that in tauopathy, PTEN has a role in the synaptotoxicity of pathological Tau and promotes microglial removal of affected neuronal structures.
Highlights
Synapse loss is the best cellular correlate of impaired cognitive function in primary tauopathies, such as frontotemporal lobar degeneration-Tau (FTLD-Tau), and Alzheimer’s disease (AD) as the major secondary tauopathy [43, 52]
Because there is evidence that synapse loss, including that in tauopathies, involves intracellular components of apoptosis [45], we investigated the role of the lipid and protein phosphatase Phosphatase and tensin homolog (PTEN) in this process
We sought to determine whether PS is exposed outside of the cell membrane in tauopathy by probing rTg4510 and WT primary neurons with the membrane asymmetry probe F2N12S, which responds to changes in the charge of the membrane following PS exposure [9, 11, 20, 25, 49]
Summary
Synapse loss is the best cellular correlate of impaired cognitive function in primary tauopathies, such as frontotemporal lobar degeneration-Tau (FTLD-Tau), and Alzheimer’s disease (AD) as the major secondary tauopathy [43, 52]. Our understanding of the process by which synapse loss occurs is limited [46]. Pathologically phosphorylated Tau progressively accumulates in the somatodendritic compartment, including synapses [19, 31, 58]. Because there is evidence that synapse loss, including that in tauopathies, involves intracellular components of apoptosis [45], we investigated the role of the lipid and protein phosphatase PTEN in this process. PTEN has been linked to neuronal apoptosis [13] and to the homeostatic regulation of dendritic spine numbers, in that a loss of PTEN causes excessive overgrowth of spines [29], whereas its overexpression results in their dramatic loss [40, 67]. PTEN activity is regulated by phosphorylation at serine (S) and threonine (T) residues which are located in its carboxyterminal domain. The enzyme further presents with a PDZ-binding domain that facilitates the interaction with adaptor proteins, such as postsynaptic density protein 95 (PSD-95) [24, 28, 67]
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