Abstract
BackgroundTau 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.MethodsThe 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.ResultsWe 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.ConclusionIn 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.
Highlights
Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies
Tau oligomers have emerged as the most toxic species in tauopathies, which cause the spreading of tau pathology, induce further tau aggregation and neuroinflammation [11]
We found that rutin improved spatial memory and reduced Aβ oligomer level and neuroinflammation in APP/PS1 mouse model of AD [14]
Summary
Abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss [1], the deposition of extracellular Aβ plaques, and intracellular neurofibrillary tangles (NFTs) composed of tau aggregates [2, 3]. During procession of AD and other tauopathies, hyperphosphorylation of tau is one of the earliest and continuous events, which disrupt the association of tau with MTs, and promote tau aggregation in neurons and relocation to synapses [7, 8]. Each stage in tau pathology, from tau expression to post-translational modifications and aggregation, or tau-induced synapse loss and neuroinflammation, presents opportunities for intervention [12]. Given tau pathology is a complex multifactorial process, strategies targeting multiple phases for therapeutic intervention might be promising
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