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Pleiotropic Neuroprotective Effects of Taxifolin in Cerebral Amyloid Angiopathy

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Pleiotropic Neuroprotective Effects of Taxifolin in Cerebral Amyloid Angiopathy Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy Takayuki Inouea, Satoshi Saitob,c, Masashi Tanakaa,d,1, Hajime Yamakagea, Toru Kusakabea, Akira Shimatsue, Masafumi Iharab, and Noriko Satoh-Asaharaa aDepartment of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Fushimi-ku, 612-8555 Kyoto, Japan; bDepartment of Neurology, National Cerebral and Cardiovascular Center, Suita, 565-8565 Osaka, Japan; cDepartment of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, 565-8565 Osaka, Japan; dDepartment of Physical Therapy, Health Science University, Fujikawaguchiko-machi, 401-0380 Yamanashi, Japan; and eClinical Research Institute, National Hospital Organization Kyoto Medical Center, Fushimi-ku, 612-8555 Kyoto, Japan Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved April 9, 2019 (received for review January 28, 2019) Cerebral amyloid angiopathy (CAA) results from amyloid-β depo- cognitive dysfunction (3, 11). However, the intracerebral mech- sition in the cerebrovasculature. It is frequently accompanied by anisms underlying the potential therapeutic effects of taxifolin Alzheimer’s disease and causes dementia. We recently demon- for CAA have not been comprehensively elucidated. strated that in a mouse model of CAA, taxifolin improved cerebral Triggering receptor expressed on myeloid cell 2 (TREM2) is a blood flow, promoted amyloid-β removal from the brain, and pre- transmembrane protein expressed exclusively on microglia in the vented cognitive dysfunction when administered orally. Here we brain. Microglia are the main cell involved in the innate immune showed that taxifolin inhibited the intracerebral production of system in the brain, and they also modulate neuroinflammatory amyloid-β through suppressing the ApoE–ERK1/2–amyloid-β pre- states (12, 13). TREM2 releases its soluble ectodomain, soluble cursor protein axis, despite the low permeability of the blood– TREM2 (sTREM2), into the extracellular space via cleavage by brain barrier to taxifolin. Higher expression levels of triggering proteases such as ADAM10 (14). Significant associations have been receptor expressed on myeloid cell 2 (TREM2) were associated reported between TREM2 variants and an increased risk for neu- with the exacerbation of inflammation in the brain. Taxifolin sup- rodegenerative diseases, including AD (12, 13). TREM2 has been pressed inflammation, alleviating the accumulation of TREM2- demonstrated to have antiinflammatory effects, mainly based on in expressing cells in the brain. It also mitigated glutamate levels vitro analyses; however, there is accumulating evidence suggesting MEDICAL SCIENCES and oxidative tissue damage and reduced brain levels of active that TREM2 and TREM2-expressing microglia may be implicated caspases, indicative of apoptotic cell death. Thus, the oral admin- in the pathology of neuroinflammation and concomitant neuro- istration of taxifolin had intracerebral pleiotropic neuroprotective degeneration in disease settings, characterized by in vivo mouse effects on CAA through suppressing amyloid-β production and models such as those for AD, tauopathy, and diet-induced obesity beneficially modulating proinflammatory microglial phenotypes. (13, 15–18). In addition, it was recently reported that sTREM2 was implicated in chronic inflammation through promotion of the sur- cerebral amyloid angiopathy | neuroprotection | taxifolin | triggering vival or activation of macrophages and microglia (19, 20). Further, receptor expressed on myeloid cell 2 it has been suggested that elevated sTREM2 levels in human ce- rebrospinal fluid reflect microglial activation and might provide a erebral amyloid angiopathy (CAA) is a cerebral small vessel novel clinical marker for neurodegenerative diseases (21). Recently, Cdisease, characterized pathologically by the deposition of we reported that serum sTREM2 levels may also have utility as a amyloid-β in the cerebrovasculature (1–3). CAA causes in- tracerebral hemorrhage and cognitive impairment in elderly Significance people and is often accompanied by Alzheimer’s disease (AD) and vascular dementia (1–3). There is therefore an urgent need Cerebrovascular amyloid-β deposition is highly implicated in for predictive markers and effective treatments for CAA. the pathogenesis of cerebral amyloid angiopathy (CAA), one of Taxifolin, also known as dihydroquercetin, is a natural bio- the major causes of dementia. We previously showed that active flavonoid found in various foods and herbs (4). The safety orally administered taxifolin, a natural bioactive flavonoid, profile of taxifolin has been established (5, 6), and taxifolin has enhanced the clearance of amyloid-β, improved cerebral blood been reported to exhibit various pharmacological effects, in- flow, and suppressed cognitive decline in a mouse model of cluding antioxidative, antinitrosative, and antiinflammatory ef- CAA. Here we investigate the in vivo effects of taxifolin on fects (7, 8). In vitro studies have demonstrated that taxifolin had intracerebral factors associated with neuronal injury in these an inhibitory effect on the aggregation of the 42-residue amyloid- mice. We find that orally administered taxifolin may have β β protein (amyloid- 1–42) involved in the pathogenesis of AD (9, neuroprotective effects through suppressing intracerebral 10), suggesting that taxifolin may have the potential to help amyloid-β production, neuroinflammation, and oxidative tissue prevent or treat AD. However, the ability of taxifolin to cross the damage, despite the low permeability of the blood–brain bar- blood–brain barrier (BBB) is limited and has been assumed to be rier to taxifolin. Our findings suggest taxifolin as a potential too low to prevent intracerebral amyloid-β aggregation (3, 4). target for clinical applications to prevent/treat CAA. We recently showed that in a mouse model of CAA, taxifolin administered orally improved cerebrovascular and cognitive Author contributions: M.T. designed research; T.I. and S.S. performed research; T.I., S.S., function (3). In vitro, taxifolin inhibited the aggregation of M.T., H.Y., T.K., A.S., M.I., and N.S.-A. analyzed data; and T.I., S.S., M.T., M.I., and N.S.-A. wrote the paper. amyloid-β1–40, a major component of vascular amyloid-β de- posits; in vivo, it reduced the levels of amyloid-β oligomers in the The authors declare no conflict of interest. This article is a PNAS Direct Submission. brain, with a concomitant increase in the levels of amyloid-β1–40 in circulation (3). This suggested that taxifolin could facilitate Published under the PNAS license. amyloid-β clearance from the brain, perhaps through the intra- 1To whom correspondence should be addressed. Email: [email protected]. mural periarterial drainage (IPAD) system, a vascular-mediated This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. amyloid-β elimination system. This could potentially maintain 1073/pnas.1901659116/-/DCSupplemental. vascular integrity, alleviate amyloid-β deposits, and prevent Published online April 29, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1901659116 PNAS | May 14, 2019 | vol. 116 | no. 20 | 10031–10038 Downloaded by guest on October 1, 2021 novel marker for cognitive impairment in Japanese patients with containing taxifolin for 7–13 mo. Hippocampus and cortex tis- nonobese type 2 diabetes (22) and in the general elderly Japanese sues were analyzed separately. population (23). However, the pathophysiological significance of To clarify the mechanisms underlying taxifolin’s effects in sup- TREM2 in CAA and the effects of taxifolin on microglial pheno- pressing cognitive decline in CAA model mice, we first investigated types have not been clarified. whether taxifolin protected their hippocampus and cortex cells In the present study, we comprehensively investigated the ef- from cell death because activation of caspase-mediated apoptotic fects of taxifolin on factors potentially implicated in neuronal pathways has previously been suggested in CAA (24). In the hip- injury, such as amyloid-β and inflammatory mediators, in a pocampus, taxifolin suppressed the formation of the active apo- mouse model of CAA, focusing on the potential pathological ptotic initiator caspase-9 to a near significant level compared with significance of TREM2. The results provide molecular evidence control (P = 0.07; Fig. 1A) and significantly suppressed the active for the beneficial effects of taxifolin on suppressing cognitive apoptotic effectors caspases 3 and 7 (25) (P < 0.05; Fig. 1 B and C). dysfunction in CAA. Extracellular deposition of amyloid-β and the intraneuronal accu- mulation of hyperphosphorylated tau (pTau) induce apoptotic cell Results deathinthebrain(26),andTg-SwDImiceshowamyloid-β accu- Taxifolin Exhibited Protective Effects on the Brain Cells of CAA Model mulation (27) but no remarkable tau pathology (28). We therefore Mice. All of the experiments used a mouse model of CAA based examined the effects of taxifolin on these factors. In the hippo- on Tg-SwDI mice (3). These were randomly divided into control campus, taxifolin significantly reduced the amount of amyloid-β1–40 and taxifolin groups and fed either standard chow or chow (the major component of vascular amyloid-β deposits) in line with Tax -+ -+ A B C Cleaved caspase 3 Cleaved caspase 7 * P = 0.07 * Cleaved caspase 9 -actin -actin
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