Clone 1 (Biotin-KGQANATR IPA(Ac)KTPPAPKTPPSS) and Clone 2 (Ac-CKGQANATRIPA(KAc)TPPAPKTPPSS-amide) antibodies were injected onto Series S Sensor Chip CM5 immobilized with anti-mouse antibody as Capture. measurements in human plasma following TBI were also collected to establish a link between trauma A2AR-agonist-1 and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. Results Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24?h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic says following TBI in PS19 mice. Conclusions The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is usually a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease. Supplementary Information The online version contains supplementary material available at 10.1186/s13024-024-00733-9. Keywords: Immunotherapy, Acetylated tau, Tauopathy, TBI, Human plasma Background Tauopathies are a group of neurodegenerative diseases characterized by brain deposition of neurofibrillary tangles (NFTs) of tau protein (the microtubule-associated protein tau). NFTs are fundamental to both primary tauopathies, such as A2AR-agonist-1 frontotemporal lobar degeneration (FTLD), and secondary tauopathies, such as Alzheimers disease (AD), traumatic brain injury (TBI), and chronic traumatic encephalopathy (CTE) [1]. Normally, tau protein binds and stabilizes neuronal microtubules. Under pathological conditions, however, hyperphosphorylated tau accumulates and forms aggregates that spread from diseased neurons to healthy neurons [2]. The extent of tau pathology closely correlates with neurodegeneration and cognitive impairment during disease progression [3], indicating that pathological tau is an important diagnostic marker and therapeutic target. Importantly, TBI specifically increases the risk of developing aging-related diseases of neurodegeneration, including AD, and tau pathology has been proposed to play a role in this phenomenon [4]. Tau undergoes various post-translational Rabbit polyclonal to IGF1R.InsR a receptor tyrosine kinase that binds insulin and key mediator of the metabolic effects of insulin.Binding to insulin stimulates association of the receptor with downstream mediators including IRS1 and phosphatidylinositol 3′-kinase (PI3K). modifications, including phosphorylation, acetylation, and ubiquitination [5, 6]. We and others have previously reported that tau is usually aberrantly acetylated in AD brains and that hyperacetylated tau is usually enriched in NFTs [7C12]. Aberrant acetylation inhibits tau ubiquitination, which in turn slows tau degradation and leads to accumulation and spread of pathogenic tau, including phosphorylated tau (p-tau) [10, 13C15]. Accumulation of acetylated-tau (ac-tau) also induces mis-sorting of tau to dendrites, which impairs synaptic plasticity and spatial memory and propagates axonal degeneration [12, 16C18]. We have also reported that hyperacetylation at lysine residue 174 (K174) promotes tau accumulation and aggregation, which increases its toxicity in vivo [10, 13]. Reducing ac-tauK174 by inhibiting tau acetyltransferase p300 using salsalate A2AR-agonist-1 reduces tau pathology and improves cognitive function in P301S tau transgenic mice, which carry a tau mutation that causes FTLD in people [13]. In addition, SIRT1, which deacetylates tau, markedly reduces propagation of tau inclusions in these same mice [15]. More recently, we reported that reducing TBI-induced neuronal tau acetylation is usually neuroprotective in TBI and has a protective role in AD pathogenesis following TBI [12]. A2AR-agonist-1 Thus, acetylated tau could represent a novel target for therapeutic intervention to treat tauopathies from a variety of etiologies. There has been considerable interest in using both active and A2AR-agonist-1 passive immunotherapy to treat patients suffering from tauopathies. Indeed, several anti-tau antibodies have been explored in animal models [19C24], and some have moved on to clinical trials [25, 26]. Thus far, most of these efforts have targeted phosphorylated tau or conformation-specific tau. Although some antibodies reduce tau pathology and improve somatosensory functions in mice, the reported efficacy to date has been minimal and often associated with severe side effects [25]. Given the multitude of pathological forms of tau that exist.
