Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia Graphical abstract Highlights d Postmortem AD and FTD brain tissues exhibit TauOassociated senescent astrocytes d Direct exposure of TauO triggers cellular senescence in cultured astrocytes d HMGB1 release is a crucial event during TauO-induced cellular senescence d HMGB1 released by senescent cells may contribute to the progression of tauopathies

Spinal synaptic plasticity is believed to drive central sensitization that underlies the persistent nature of neuropathic pain. Our recent data showed that synaptic plasticity in the dorsal horn is cell type-specific: intense afferent stimulation produced long-term potentiation (LTP) in excitatory spinothalamic tract neurons (STTn), whereas it produced long-term depression (LTD) in inhibitory GABAergic interneurons (GABAn). In addition, reactive oxygen species (ROS) were shown to be involved in LTP in STTn (STTn-LTP) as well as in LTD in GABAn (GABAn-LTD). This study examined the roles of two biologically important ROS—superoxide [·O2] and hydroxyl radicals [·OH]—in neuropathic mechanical hyperalgesia and cell type-specific spinal synaptic plasticity. A [·O2] donor induced stronger mechanical hyperalgesia than a [·OH] donor in naïve mice. A [·O2] scavenger showed greater anti-hyperalgesic effect than [·OH] scavengers in the spinal nerve ligation (SNL) mouse model of neuropathic pain. Moreover, a [·O2] donor induced STTn-LTP and GABAn-LTD, but a [·OH] donor induced only GABAn-LTD. In addition, a [·O2] scavenger inhibited STTn-LTP and GABAn-LTD induction (via conditioning stimulus (CS)) in naïve mice and alleviated SNL-induced potentiation and depression, respectively. Also, [·OH] scavenger selectively inhibited GABAn-LTD induction and maintenance as well as SNL-induced depression. These results indicate that mechanical hyperalgesia in SNL mice is the result of the combination of STTn-LTP and GABAn-LTD. Behavioral outcomes compliment electrophysiological results which suggest that [·O2] mediates both STTn-LTP and GABAn-LTD, whereas [·OH] is involved primarily in GABAn-LTD.

This study shows that the direction of synaptic plastic changes in the spinal cord is cell-type specific in response to nociceptive input.

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With increasing age, as the incidence of Alzheimer’s disease is increasing, finding a therapeutic intervention is becoming critically important to either prevent or slow down the progression of the disease. Passive immunotherapy has been demonstrated as a successful way of reducing large aggregates and improving cognition in animal models of both tauopathies and Alzheimer’s disease. However, with all the continuous attempts and significant success of immunotherapy in preclinical studies, finding a successful clinical therapy has been a great challenge, possibly indicating a lack of accuracy in targeting the toxic species. Both active and passive immunotherapy approaches in transgenic animals have been demonstrated to have pros and cons. Passive immunotherapy has been favored and many mechanisms have been shown to clear toxic amyloid and tau aggregates and improve memory. These mechanisms may differ depending on the antibodie's' target and administration route. In this regard, deciding on affinity vs. specificity of the antibodies plays a significant role in terms of avoiding the clearance of the physiological forms of the targeted proteins and reducing adverse side effects. In addition, knowing that a single protein can exist in different conformational states, termed as strains, with varying degrees of neurotoxicity and seeding properties, presents an additional level of complexity. Therefore, immunotherapy targeting specifically the toxic strains will aid in developing potential strategies for intervention. Moreover, an approach of combinatorial immunotherapies against different amyloidogenic proteins, at distinct levels of the disease progression, might offer an effective therapy in many neurodegenerative diseases.