Protective Effect of Genistein against Neuronal Degeneration in ApoE−/− Mice Fed a High-Fat Diet

Abstract

Altered cholesterol metabolism is believed to play a causal role in major pathophysiological changes in neurodegeneration. Several studies have demonstrated that the absence of apolipoprotein E (ApoE), a predominant apolipoprotein in the brain, leads to an increased susceptibility to neurodegeneration. Previously, we observed that genistein, a soy isoflavone, significantly alleviated apoptosis and tau hyperphosphorylation in SH-SY5Y cells. Therefore, we investigated the neuroprotective effects of dietary genistein supplementation (0.5 g/kg diet) in the cortex and hippocampus of wild-type C57BL/6 (WT) and ApoE knockout (ApoE−/−) mice fed a high-fat diet (HFD) for 24 weeks. Genistein supplementation alleviated neuroinflammation and peripheral and brain insulin resistance. Reductions in oxidative and endoplasmic reticulum stress were also observed in ApoE−/− mice fed a genistein-supplemented diet. Beta-secretase 1 and presenilin 1 mRNA levels and beta-amyloid peptide (Aβ) protein levels were reduced in response to genistein supplementation in ApoE−/− mice but not in WT mice. Although the absence of ApoE did not increase tau hyperphosphorylation, genistein supplementation reduced tau hyperphosphorylation in both WT and ApoE−/− mice. Consistent with this result, we also observed that genistein alleviated activity of c-Jun N-terminal kinase and glycogen synthase kinase 3β, which are involved in tau hyperphosphorylation. Taken together, these results demonstrate that genistein alleviated neuroinflammation, Aβ deposition, and hyperphosphorylation in ApoE−/− mice fed an HFD.

Genistein Modifies Hamster Behavior and Expression of Inflammatory Factors following Subchronic Unpredictable Mild Stress

“…Even diminished motor performances detected in HB test along with increased head dip latency plus a pro-inhibiting activity consisting of reduced head dip duration/counts and rearing, which support anxiogenic states, tend to corroborate reduced motivational plus explorative stimuli [24]. Interestingly, all behavioral exploratory events seemed to be largely rescued following treatment with genistein, as suggested by this phytoestrogenic hormone diminishing anxiety and depression episodes [7, 25]. …”

“…To date, growing indications are rapidly suggesting genistein (4′,5,7-trihydroxyisoflavone), which is plentiful in soybeans, as a major isoflavonoid capable of modifying hypothalamic structural and functional features by exerting key regulatory role(s) on hormonal secretion activities [6] as well as diminished brain inflammatory processes [7]. Based on such features, neurogenic events of the hippocampus (HIP) and the hypothalamus (HTH) seem to comprise a key target of phytoestrogenic neuroprotective actions, especially in view of the negative relationship between neurogenesis and depression/anxiety features of such regions [8].…”

Nonpharmacological treatment options for Alzheimer’s disease: from animal testing to clinical studies

“…Reducing Aβ1-42 accumulation and levels of APP, inhibiting BACE1 activity (Liu et al, 2017) Curcumin Activating neuronal nitric oxide pathway Caffeic acid Blocking Aβ formation and aggregation (Habtemariam, 2016) Epigallocatechin Modulating the enzymes involved in APP processing and reducing the formation of Aβ (Rezai-Zadeh, 2005) Ferulic acid Exerting antiinflammatory actions (Ghosh et al, 2017) Gallic acid Preventing fibril formation by Aβ peptide (Liu et al, 2013) Genistein Modulating neuroinflammation, Aβ deposition, and tau hyperphosphorylation (Park et al, 2016) Hesperidin Exhibiting high-affinity BACE1 inhibitor, preventing Aβ fibril formation (Chakraborty et al, 2016) Honokiol Modulating excitotoxicity associated with the blockade of glutamate receptors and reducing neuroinflammation (Talarek et al, 2017) Icariin Preventing Aβ1-42 aggregation (Liu et al, 2015) Leucomicin Preventing Aβ1-42 induced oxidative stress (Türkez, 2018) Lycopene Inhibiting NF-κB activity and regulating neuroinflammatory cytokines (Sachdeva and Chopra, 2015) Naringenin Alleviating Aβ-induced impairments, lipid peroxidation, and apoptosis via the estrogenic pathway. (Ghofrani et al, 2015) Nobiletin Reducing Aβ plaques, NFTs, and cognitive impairments (Nakajima et al, 2015) Oleuropein Counteracting amyloid-β peptide and tau aggregation (Martorell et al, 2016) Quercetin Minimizing Aβ1-40 and Aβ1-42 amounts, decreasing BACE1-mediated cleavage of APP (Sabogal-Guáqueta et al, 2015) Rosmarinic acid Preventing Aβ-sheet assembly (Cornejo et al, 2017) Resveratrol Promoting the removal of Aβ peptides and antiinflammatory content (Braidy et al, 2016) Rutin Inhibiting Aβ aggregation, supporting antioxidant SOD, CAT, and GSH-Px enzyme activities (Yu et al, 2015) Sulforaphane Reducing cholinergic neuron loss (Zhang et al, 2014) Tangeretin Alleviating cholinergic deficits, reducing Aβ accumulation, inhibiting tau hyperphosphorylation and increasing NEP levels (Braidy et al, 2017a) Tannic acid…”

Molekularne mechanizmy działania genisteiny w świetle terapii chorób genetycznych i immunologicznych

“…Jednakże podanie genisteiny zmniejsza poziom białek: βA oraz APP. Ponadto pod wpływem opisywanego flawonoidu dochodzi do obniżenia poziomu enzymów biorących udział w powstawaniu βA (BACE1, γ-sekretazy) [66]. Badania nad myszami z hipercholesterolemią wykazały, że genisteina znosi efekty zaburzenia metabolizmu cholesterolu, który ma związek z akumulacja βA.…”

“…Badania nad myszami z hipercholesterolemią wykazały, że genisteina znosi efekty zaburzenia metabolizmu cholesterolu, który ma związek z akumulacja βA. Izoflawon ten obniża poziom ekspresji genów zarówno APP, jak i aktywność kinaz odpowiedzialnych za fosforylację białka tau (kinaza GSK-3β i JNK) [66]. Kolejne badania nad mysim modelem AD wykazały, że genisteina aktywuje inne ugrupowanie receptora PPARγ [67].…”