Autophagy-dependent mechanism of genistein-mediated elimination of behavioral and biochemical defects in the rat model of sporadic Alzheimer's disease

Pierzynowska, Karolina; Podlacha, Magdalena; Gaffke, Lidia; Majkutewicz, Irena; Mantej, Jagoda; Węgrzyn, Alicja; Osiadły, Marta; Myślińska, D.; Węgrzyn, Grzegorz

doi:10.1016/j.neuropharm.2019.01.030

Cited by 72 publications

(48 citation statements)

References 47 publications

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“…17,53 The autophagy-dependent mechanism may also be responsible for regulating the concentrations of hyperphosphorylated Tau by genistein in AD mice. 54 In addition, a recent study demonstrated that the hyperphosphorylation of Tau in the brain of ob/ob mice might relate to hypothermia and the decreased thyroid hormone levels. 55 Interestingly, treatment of ob/ob mice with genistein elevated thyroid hormone levels and induced a thermogenic change in these mice, 25 suggesting that genistein might be a novel therapy in the elimination of hyper-phosphorylated Tau.…”

Section: Discussionmentioning

confidence: 99%

<p>Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model</p>

Li¹,

Ding²,

Geetha³

et al. 2020

DDDT

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Purpose: Diabetes mellitus (DM)-induced brain damage is characterized by cellular, molecular and functional changes. The mechanisms include oxidative stress, neuroinflammation, reduction of neurotrophic factors, insulin resistance, excessive amyloid beta (Aβ) deposition and Tau phosphorylation. Both antidiabetic and neuroprotective effects of the phytoestrogen genistein have been reported. However, the beneficial effect of genistein in brain of the ob/ob mouse model of severe obesity and diabetes remains to be determined. Methods: In this study, female ob/ob mice and lean control mice were fed with either a standard diet or a diet containing genistein (600mg/kg) for a period of 4 weeks. Body weight was monitored weekly. Blood was collected for the measurement of glucose, insulin and common cytokines. Mice brains were isolated for Western immunoblotting analyses. Results: Treatment with genistein reduced weight gain of ob/ob mice and decreased hyperglycemia compared to ob/ob mice fed the standard diet. The main findings show that genistein treatment increased insulin sensitivity and the expression levels of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF). In these mice, genistein also reduced Aβ deposition and the level of hyper-phosphorylated Tau protein. Conclusion: The results of our study indicate the beneficial effects of genistein in the obese diabetic mouse brain, including improving brain insulin signaling, increasing neurotrophic support, and alleviating Alzheimer's disease-related pathology.

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Section: Discussionmentioning

confidence: 99%

<p>Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model</p>

Li¹,

Ding²,

Geetha³

et al. 2020

DDDT

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show abstract

“…To reduce synaptic defect and neuronal death, clearance of Aβ from the brain is another main target for anti-AD drugs [202]. In the study of Pierzynowska et al [203], it was shown that at a high dose (i.e., 150 mg/kg/day), genistein caused activation of autophagy in a streptozotocin-induced rat model of the sporadic AD. Moreover, at this high dose, the authors also noticed that genistein triggered the complete degradation of Aβ and hyperphosphorylated tau via induction of autophagy [203].…”

Section: Role Of Flavonoids In Autophagymentioning

confidence: 99%

Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer’s Disease

et al. 2020

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Alzheimer’s disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aβ) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aβ peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aβ peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer’s pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

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“…Aβ clearance from the brain is another major target for anti-AD drugs in order to decrease neuronal death and synaptic defect (Lukiw, 2012; Uddin et al, 2019c). It has been revealed by Pierzynowska et al (2019) that genistein can cause activation of autophagy at the higher dose (i.e., 150 mg/kg per day; this dose was markedly higher as compared to the doses used in previous AD studies) in a streptozotocin-induced rat model of the sporadic AD. In addition to this, they also observed that at this dose, genistein caused complete degradation of Aβ and hyperphosphorylated tau by stimulation of autophagy.…”

Section: Anti-alzheimer’s In Vivo Studies Of Genisteinmentioning

confidence: 90%

Emerging Signal Regulating Potential of Genistein Against Alzheimer’s Disease: A Promising Molecule of Interest

Uddin

Kabir

2019

Front. Cell Dev. Biol.

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Alzheimer’s disease (AD) is a progressive, irreversible brain disorder characterized by pathological aggregation of the amyloid-β peptide (Aβ) and tau protein; both of these are toxic to neurons. Currently, natural products are regarded as an alternative approach to discover novel multipotent drugs against AD. Dietary soy isoflavone genistein is one of the examples of such agents that occurs naturally and is known to exert a number of beneficial health effects. It has been observed that genistein has the capacity to improve the impairments triggered by Aβ and also it possesses the antioxidant potential to scavenge the AD-mediated generation of free radicals. Furthermore, genistein can interact directly with the targeted signaling proteins and also can stabilize their activity to combat AD. In order to advance the development of AD treatment, a better comprehension of the direct interactions of target proteins and genistein might prove beneficial. Therefore, this article focuses on the therapeutic effects and molecular targets of genistein, which has been found to target directly the Aβ and tau to control the intracellular signaling pathways responsible for neurons death in the AD brain.

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Autophagy-dependent mechanism of genistein-mediated elimination of behavioral and biochemical defects in the rat model of sporadic Alzheimer's disease

Cited by 72 publications

References 47 publications

<p>Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model</p>

<p>Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model</p>

Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer’s Disease

Emerging Signal Regulating Potential of Genistein Against Alzheimer’s Disease: A Promising Molecule of Interest

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