Patient-derived tau and amyloid-β facilitate long-term depression in vivo: role of tumour necrosis factor-α and the integrated stress response

Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-beta and tau. It is well documented that synaptotoxic soluble amyloid-beta aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-beta were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-beta. In vivo electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-beta were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-alpha or the integrated stress response to prevent the effects of amyloid-beta or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-beta and synthetic oligomeric amyloid-beta, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-beta was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-alpha and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-beta. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-beta. Pharmacologically targeting shared mechanisms of tau and amyloid-beta synaptotoxicity, such as tumour necrosis factor-alpha or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease. Hu et al. report that Alzheimer's disease-related proteins tau and amyloid-beta both facilitate synaptic long-term depression, a process by which synapses become less efficient in transmitting neuronal signals. Thus, targeting common pathways of both proteins could be a promising approach for Alzheimer's disease treatment. Graphical abstract