7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer’s disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance

Akhtar, Ansab; Dhaliwal, Jatinder; Sah, Sangeeta Pilkhwal

doi:10.1007/s00213-021-05826-7

Cited by 53 publications

(32 citation statements)

References 65 publications

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“…Consistent with the pivotal role of ATP-producing mitochondria in energy-demanding synaptic terminals, the expression of two key synaptic proteins-such as synapsin I and α-synuclein known to be imbalanced in hippocampus of STZ-injected mice in association with poor behavioral performance [78,109]-is also normalized by in vivo neutralization of the NH 2 htau. Additionally, our morphological results combining hematoxylin and eosin (H&E) staining and immunofluorescence analysis also confirmed that a significant increase in the number of darkly stained, apoptotic neurons was evident in different hippocampal regions of STZ-lesioned mice, as reported by previous histopathological investigations [84,85], and that neutralization of the endogenously generated toxic NH 2 htau following 12A12mAb immunization provided a marked in vivo protection from cell de-generation. These findings indicate that the neuroprotective effect of tau immunization involves, in part, the modulation of oxidative stress and mitochondrial energetic deficits, which are known to crucially contribute to the age-related synaptic decline of sAD in humans [110].…”

Section: Discussionsupporting

confidence: 87%

“…lesioned mice, as reported by previous histopathological investigations [84,85], and that neutralization of the endogenously generated toxic NH2htau following 12A12mAb immunization provided a marked in vivo protection from cell degeneration. These findings indicate that the neuroprotective effect of tau immunization involves, in part, the modulation of oxidative stress and mitochondrial energetic deficits, which are known to crucially contribute to the age-related synaptic decline of sAD in humans [110].…”

Section: Discussionsupporting

confidence: 82%

“…Collectively, these results showed that some histopathological alterations typically detected in hippocampus of ICV-STZ mice [84,85] are significantly ameliorated in vivo by 12A12mAb-mediated neutralization of the toxic, endogenously generated NH 2 htau. the distribution/expression of the NH 2 htau peptide (green channel) in hippocampal CA3 regions from animals of four experimental groups (STZ 0 plus vehicle; STZ 0 plus mAb; STZ 3 plus vehicle; STZ 3 plus mAb).…”

Section: Stz-induced Histopathologic Alterations Are Improved In the Hippocampus Of Injected Mice Following 12a12mab Immunizationmentioning

confidence: 70%

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Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

Latina

Giacovazzo

Calissano

et al. 2021

IJMS

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Tau cleavage plays a crucial role in the onset and progression of Alzheimer’s Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)—a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance—mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it’s in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 82%

Section: Stz-induced Histopathologic Alterations Are Improved In the Hippocampus Of Injected Mice Following 12a12mab Immunizationmentioning

confidence: 70%

See 1 more Smart Citation

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

Latina

Giacovazzo

Calissano

et al. 2021

IJMS

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“…In contrast, the pathophysiology of the ICV-STZ animal model is similar to that of AD patients [ 47 ]. Furthermore, ICV-STZ has now been found to induce cognitive impairment and neuron damage [ 48 ], oxidative stress [ 49 ] and glucose/energy metabolism damage in the brain [ 50 ], insulin resistance in the brain [ 51 , 52 ], and finally lead to Tau hyperphosphorylation and Aβ deposition [ 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Shen Qi Wan Ameliorates Learning and Memory Impairment Induced by STZ in AD Rats through PI3K/AKT Pathway

Huang

Chen

et al. 2022

Brain Sciences

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Alzheimer’s disease is the most common form of neurodegenerative disease, and increasing evidence shows that insulin signaling has crucial roles in AD initiation and progression. In this study, we explored the effect and underlying mechanism of SQW, a representative formula for tonifying the kidney and promoting yang, on improving the cognitive function in a streptozotocin-induced model of AD rats. We investigated memory impairment in the AD rats by using the Morris water test. HE and Nissl staining were employed to observe the histomorphological changes in the hippocampal. Expression levels of NeuN and proteins related to Tau and apoptosis were measured using immunohistochemistry and Western blotting, respectively. Additionally, we performed RNA sequencing, and the selected hub genes were then validated by qRT-PCR. Furthermore, the protein expression levels of PI3K/AKT pathway-related proteins were detected by Western blot. We found that SQW treatment significantly alleviated learning and memory impairment, pathological damage, and apoptosis in rats, as evidenced by an increased level of NeuN and Bcl-2, and decreased phosphorylation of Tau, Bax, and Caspase-3 protein expression. SQW treatment reversed the expression of insulin resistance-related genes (Nr4a1, Lpar1, Bdnf, Atf2, and Ppp2r2b) and reduced the inhibition of the PI3K/AKT pathway. Our results demonstrate that SQW could contribute to neuroprotection against learning and memory impairment in rats induced by STZ through activation of the PI3K/AKT pathway.

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“…Further evidence speculated that the homeostasis imbalance of downstream metabolites regulated by microglia and astrocytes might be the prominent mechanism of depressive behaviors after IDO activation induced by LPS (Tao, Yan et al, 2020). Intracerebroventricular injection of streptozotocin (ICV-STZ) triggered progressive mood and cognitive impairments by causing Aβ-Tau pathology, oxidative stress, insulin resistance and immune-inflammatory responses in the cerebral cortex and hippocampus of rats (Akhtar, Dhaliwal et al, 2021;Grieb, 2016). Souza et al reported that ICV-STZ can induce up-regulation of pro-inflammatory cytokines and down-regulation of brain-derived neurotrophic factor (BDNF) in the hippocampus of mice at the early stage of the formation of a sporadic Alzheimer's disease (sAD) model (Souza, Filho et al, 2013;Souza, Jesse et al, 2017), and subcutaneous administration of IDO inhibitor 1-MT improved depressive behaviors in ICV-STZ mice (Souza, Jesse et al, 2017).…”

mentioning

confidence: 99%

Inhibition of indoleamine 2, 3-dioxygenase in prelimbic or infralimbic cortex of ICV-STZ rats can exert antidepressant effects through different pathways

Cui

et al. 2022

Preprint

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Background and purpose Activation of indoleamine 2,3-dioxygenase (IDO) in prefrontal cortex (PFC) is closely related to depression. It has been proved that prelimbic (PrL) and infralimbic (IL) regions of medial PFC are involved in emotion regulation, and may play distinct roles in regulation of depression. However, the mechanism of how IDO in PrL or IL affects depressive behaviors remains unclear. Experimental approach IDO inhibitor 1-MT was directly injected into PrL and IL of depressive rats induced by ICV-STZ, respectively. Depressive-and anxiety-behaviors were evaluated in forced swim test, sucrose preference test, novelty-suppressed feeding test, novel object recognition test and open field test. HPLC-MS/MS detected kynurenine metabolites, ELISA detected cytokines, Western blot examined protein expression and Golgi staining assessed synaptic plasticity. Immunofluorescence staining was used to observe the expression and morphology of glial cells. Key results Dissimilar abnormalities were observed in PrL and IL of ICV-STZ depressed rats. In PrL, astrocyte defects were manifested, including reduced GFAP-positive cells, glial transporters and kynurenic acid, and morphological damage. In IL, microglial overactivation was manifested by increased cytokines, Iba1-positive cells and 3-hydroxy-kynurenine, accompanied by morphological alterations. Meanwhile, synaptic plasticity was decreased in both subregions. Microinjection of 1-MT at PrL or IL may improve depressive behaviors by reversing these different abnormalities in PrL and IL, respectively, without influencing anxiety behavior. Conclusions and implications Overall, the antidepressant effects of 1-MT by inhibiting IDO in PrL or IL are realized through different pathways, that is, by enhancing neuroprotective effects in PrL and attenuating neurotoxic response in IL.

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7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer’s disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance

Cited by 53 publications

References 65 publications

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

Shen Qi Wan Ameliorates Learning and Memory Impairment Induced by STZ in AD Rats through PI3K/AKT Pathway

Inhibition of indoleamine 2, 3-dioxygenase in prelimbic or infralimbic cortex of ICV-STZ rats can exert antidepressant effects through different pathways

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