PTEN activation as an early indicator of synaptic dysfunction priming synapses for microglial engulfment Benetatos J, Ellis S, Bodea LG, Götz J Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Australia
Hallmarks of Alzheimer's disease (AD) are extracellular plaques composed of amyloid- and intracellular neurofibrillary tangles composed of tau. An early functional consequence of these pathologies is synaptic dysfunction, in the form of increased long term synaptic depression (LTD), thought to be the effect of N-methyl-D-aspartate receptor (NMDAR)- mediated and pathological tau-dependent over-excitation. In AD, synaptic dysfunction is followed first by synaptic and then neuronal loss. Several proteins that are involved in facilitating LTD are also involved in apoptosis, a form of programmed cell death. The lipid phosphatase PTEN is an NMDAR activity driven regulator of LTD, which functions in apoptosis by antagonizing the pro-survival pathway. While the link between LTD and apoptosis has not been fully established, we hypothesize that these events converge via PTEN as an activity-dependent mechanism of synapse removal. Using the rTg4510 mouse model which overexpresses human tau harbouring the frontotemporal dementia (FTD) mutation P301L, we found increased synaptosomal activity of PTEN compared to age-matched wild-type controls. A synaptic increase in PTEN activity was found as early as 2 months of age and was maintained at both 6 and 12 months, while measurements of PTEN activity in total brain lysates revealed increased activity only at the later time-points. Interestingly, PTEN activity in synaptosomes occurred prior to detectable changes in the cleavage of caspase-3 and exposure of phosphatidylserine, both established markers of apoptosis. Additionally, we detected postsynaptic density protein 95 (PSD-95) in microglial lysosomes starting at 2 months, whereas at 6 months we detected both PSD-95 and the neuronal cell body-specific microtubule-associated protein 2 (MAP2) in the lysosomes, suggesting that synapses are specifically pruned at disease onset, while dendrites and entire neurons are engulfed as AD progresses. Our data suggest that tau-mediated synaptic dysfunction is gated by PTEN and that it triggers a synapse-specific type of apoptosis that eventually affects the entire neuron, promoting its removal by microglia.
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