Tannic Acid Is a Natural β-Secretase Inhibitor That Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice

Mori, Takashi; Rezai‐Zadeh, Kavon; Naoki, Katsuhiko; Arendash, Gary W.; Yamaguchi, Hideyo; Kakuda, Nobuto; Horikoshi-Sakuraba, Yuko; Tan, Jun; Town, Terrence

doi:10.1074/jbc.m111.294025

Cited by 166 publications

(117 citation statements)

References 75 publications

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“…This behavioral phenotype has been reported in cerebral amyloidosis mouse models (e.g. Tg2576 or PSAPP mice) (20,22,23,26,35), and it may reflect disinhibition because of cortical and/or hippocampal damage (25). Overall ANOVA disclosed the main effects of genotype (p Ͻ 0.001 for both locomotion and rearing scores) and treatment (p Ͻ 0.001 for both locomotion and rearing scores), and repeated-measures ANOVA followed by post hoc comparison revealed statistically significant differences between PSAPP-V mice and the other three groups of mice for both locomotion and rearing scores (Fig.…”

Section: Methylene Blue Treatment Reverses Behavioral Benefits Insupporting

confidence: 72%

“…Aged PSAPP mice had typical cerebral ␤-amyloid deposits (17,18,22,23). In fact, PSAPP-V mouse brains had 7.1-8.6% of cerebral ␤-amyloid burden at 18 months of age that distributed diffusely throughout RSC, EC, and H regions and was markedly and significantly reduced by 3.1-5.8% in all three PSAPP-MB brain regions, with greatest reduction in the EC (Figs.…”

Section: Methylene Blue Treatment Reverses Behavioral Benefits Inmentioning

confidence: 99%

“…According to previously described methods (22,23,26,36,37), ␤-amyloid deposits were assigned to one of three mutually exclusive categories according to maximum diameter as follows: small (Ͻ 25 m), medium (between 25 and 50 m), or large (Ͼ 50 m). Mean numbers of deposits in all three subsets showed statistically significant decreases in PSAPP-MB versus PSAPP-V mice across all three brain regions examined, with the greatest reduction in the large sized subset, especially in the EC (Figs.…”

Section: Methylene Blue Treatment Reverses Behavioral Benefits Inmentioning

confidence: 99%

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Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

Mori¹,

Naoki

Segawa

et al. 2014

Journal of Biological Chemistry

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Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene-associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway.

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Section: Methylene Blue Treatment Reverses Behavioral Benefits Insupporting

confidence: 72%

Section: Methylene Blue Treatment Reverses Behavioral Benefits Inmentioning

confidence: 99%

Section: Methylene Blue Treatment Reverses Behavioral Benefits Inmentioning

confidence: 99%

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Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

Mori¹,

Naoki

Segawa

et al. 2014

Journal of Biological Chemistry

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“…65 Also, brain parenchymal and cerebral vascular β-amyloid deposits were diminished in tannic acid treated PSAPP mice, suggesting that it acts as a natural β-secretase inhibitor. 66 Natural flavonoids were shown to potently inhibit BACE-1 activity and reduce the level of secreted Aβ in primary cortical neurons, 67 whereas epigallocatechin-3-gallate and curcumin suppress amyloid beta-induced BACE-1 upregulation in neuronal cultures. 68 Several studies have focused on studying the beneficial properties of regular intake of green tea.…”

Section: ■ Flavonoidsmentioning

confidence: 99%

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Baptista

Henriques

Silva

et al. 2014

ACS Chem. Neurosci.

167

111

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Alzheimer's disease is characterized by pathological aggregation of protein tau and amyloid-β peptides, both of which are considered to be toxic to neurons. Naturally occurring dietary flavonoids have received considerable attention as alternative candidates for Alzheimer's therapy taking into account their antiamyloidogenic, antioxidative, and anti-inflammatory properties. Experimental evidence supports the hypothesis that certain flavonoids may protect against Alzheimer's disease in part by interfering with the generation and assembly of amyloid-β peptides into neurotoxic oligomeric aggregates and also by reducing tau aggregation. Several mechanisms have been proposed for the ability of flavonoids to prevent the onset or to slow the progression of the disease. Some mechanisms include their interaction with important signaling pathways in the brain like the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate prosurvival transcription factors and gene expression. Other processes include the disruption of amyloid-β aggregation and alterations in amyloid precursor protein processing through the inhibition of β-secretase and/or activation of α-secretase, and inhibiting cyclin-dependent kinase-5 and glycogen synthase kinase-3β activation, preventing abnormal tau phosphorylation. The interaction of flavonoids with different signaling pathways put forward their therapeutic potential to prevent the onset and progression of Alzheimer's disease and to promote cognitive performance. Nevertheless, further studies are needed to give additional insight into the specific mechanisms by which flavonoids exert their potential neuroprotective actions in the brain of Alzheimer's disease patients. KEYWORDS: Flavonoids, Alzheimer's disease, amyloid precursor protein, amyloid beta, BACE-1, tau, signaling A lzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia worldwide. The major histopathological hallmarks of AD include proteinous aggregates in the form of neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau 1,2 and extracellular senile plaques, which are deposits of heterogeneously sized small peptides of amyloid-β (Aβ) that are formed via sequential proteolytic cleavages of the amyloid precursor protein (APP) 3 (Figure 1). Dominant mutations in APP, presenilin-1 (PS1) or PS2 are responsible for the early onset or familial form of AD. These mutations have been shown to profoundly alter APP metabolism, favoring the production of aggregation-prone Aβ species, these findings formed the basis for the "amyloid cascade hypothesis" of AD pathogenesis. This broadly accepted hypothesis states that the generation of neurotoxic Aβ peptides by β-secretase and γ-secretase are at the basis of AD pathophysiology. Other hallmarks of this disease, like neurotransmitter changes 4,5 and neuronal and synapse loss in the neocortex and the hippocampus 6,7 develop as a consequence of this event.■ AMYLOID PRECURSOR PROTEIN APP belongs to a protein f...

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“…Although the exact mechanisms underlying these improvements are not clear, it has been suggested that polyphenols may delay the initiation of and/or slow the progression of Alzheimer's Disease (AD)-like pathology, including a potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g. oxidative stress and neuroinflammation) (Vauzour et al, 2007a;Mori et al, 2012;Cox et al, 2015). Polyphenols can reduce amyloid-beta (Ab) plaque pathology (Hirohata et al, 2007;Amit et al, 2008;Ehrnhoefer et al, 2008;Ono et al, 2008;Wang et al, 2014), and therefore they could have utility in AD beyond anti-Ab processing .…”

Section: Effects Of Polyphenols On Age-related Cognitive Decline and mentioning

confidence: 99%

Polyphenols and brain health

Vauzour

2017

OCL

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-Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related health disorders and to improve cognitive function. A growing number of dietary intervention studies in humans and animals and in particular those using polyphenol-rich diets have been proposed to exert a multiplicity of neuroprotective actions within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation and a potential to promote memory, learning, and cognitive functions. These effects appear to be underpinned by two common processes. First, they are capable of interactions with critical protein and lipid kinase signalling cascades in the brain, leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and synaptic plasticity. Second, they induce beneficial effects on the vascular system, leading to changes in cerebrovascular blood flow capable of causing enhance vascularisation and neurogenesis, two events important in the maintenance of cognitive performances. Together, these processes act to maintain brain homeostasis and play important roles in neuronal stress adaptation and thus polyphenols might have the potential to prevent the progression of neurodegenerative pathologies.

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Tannic Acid Is a Natural β-Secretase Inhibitor That Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice

Cited by 166 publications

References 75 publications

Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

Polyphenols and brain health

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