Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease

Abstract

Background Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. Methods The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. Results We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. Conclusion In combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ.

Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease

“…We further found that AD individuals with increased t-tau also showed increased cytokine signaling and leukocyte activation. This activation could result from soluble tau oligomers, [ 97 ] although it is also possible that both increased t-tau levels and microglia activation result from amyloid pathology.…”

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model

“…NF-κB, a key transcription factor, promotes the proinflammatory M1 activation of microglia [ 64 ]. Recent studies have shown that targeting microglia may produce more beneficial therapeutic outcomes [ 13 , 65 , 66 ]. In this work, based on the phenotypic screening assay against microglia neuroinflammation, we firstly screened out a hit OABL with strong anti-neuroinflammatory effect, low cytotoxicity, good BBB penetration and ADMET properties from 4207 small compounds ( Fig.…”

Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

“…This mechanism is likely involved in the high inhibition of hippocampal LTP seen by Ondrejcak et al [135]. Promisingly, a new pharmacological treatment promotes the microglial-mediated engulfment of extracellular tau oligomers and therefore blocks the spreading of tau pathology within neurons [82]. This achievement opens new lines of investigation addressing the blockage of aberrant tau dissemination once it is released to the extracellular space.…”

“…Although tau has been considered an axonal microtubule-associated protein for many years [77], recent advances have demonstrated that tau plays important roles as a synaptic protein, since changes in its structure or expression affect synaptic plasticity [78][79][80][81][82].…”

“…The increase in hyperphosphorylated tau at dendrites triggers different pathways underlying pathological synapse weakening. For example, it has been reported that there is a specific pruning of asymmetric synapses that is carried out by microglia and induced by hyperphosphorylated tau [80,82]. Besides, aberrant tau is critically involved in the turnover and trafficking of NMDA and AMPARs related to the blockade of asymmetric LTP.…”