Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model

Kimura, Ryuji; Ohno, Minoru

doi:10.1016/j.nbd.2008.10.006

Cited by 273 publications

(264 citation statements)

References 52 publications

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“…We also tested PPF, which represents a short-term form of synaptic plasticity reflecting presynaptic function. Consistent with the previous report that PPF was not affected in 5XFAD mice (Kimura and Ohno, 2009), we found that the ratio of paired pulse was similar when comparing nontransgenic control, vehicle-and 7,8-DHF-treated 5XFAD (Figure 5b). Then we tested the basal synaptic transmission at CA1 synapses by measuring the input/ output (I/O) curves.…”

Section: Chronic Oral Administration Of 78-dhf Restores Synaptic Plasupporting

confidence: 92%

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7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

Zhang

Liu

Schroeder

et al. 2013

Neuropsychopharmacol

213

189

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Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor/ tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Abinduced toxicity and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Ab deposition in transgenic mice that coexpress five familial Alzheimer's disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.

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Section: Chronic Oral Administration Of 78-dhf Restores Synaptic Plasupporting

confidence: 92%

“…5XFAD mice show significantly impaired LTP at the Schaffer collateral-CA1 pathways compared with non-transgenic mice (Kimura and Ohno, 2009). We examined whether chronic oral 7,8-DHF treatment can rescue LTP deficit observed in hippocampal slices from 5-month-old 5XFAD mice.…”

Section: Chronic Oral Administration Of 78-dhf Restores Synaptic Plamentioning

confidence: 99%

7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

Zhang

Liu

Schroeder

et al. 2013

Neuropsychopharmacol

213

189

View full text Add to dashboard Cite

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“…5XFAD mice start to develop visible amyloid deposition as early as 2 months of age consistent with their dramatically accelerated Ab42 production because of a combination of the multiple FAD mutations, thus representing an early onset and aggressive amyloid mouse model . At 4-6 months of age, 5XFAD mice start to show impairments in hippocampus-dependent learning and memory as tested by the Y-maze, Morris water maze, and contextual or trace fear conditioning paradigms (Kimura and Ohno, 2009;Oakley et al, 2006;Ohno et al, 2006). These behavioral deficits are observed concomitant with the onset of hippocampal CA1 synaptic dysfunctions such as reduced basal transmission and long-term potentiation (LTP: a synaptic plasticity model for learning and memory) (Kimura and Ohno, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…At 4-6 months of age, 5XFAD mice start to show impairments in hippocampus-dependent learning and memory as tested by the Y-maze, Morris water maze, and contextual or trace fear conditioning paradigms (Kimura and Ohno, 2009;Oakley et al, 2006;Ohno et al, 2006). These behavioral deficits are observed concomitant with the onset of hippocampal CA1 synaptic dysfunctions such as reduced basal transmission and long-term potentiation (LTP: a synaptic plasticity model for learning and memory) (Kimura and Ohno, 2009). Furthermore, 5XFAD mice begin to exhibit elevations in expression levels of the b-secretase (b-site APP cleaving enzyme 1: BACE1), which is responsible for initiating the production of Ab, at 6-9 months of age (Devi and Ohno, 2010b;Ohno et al, 2007;Zhang et al, 2009;Zhao et al, 2007), as observed in sporadic AD brains (Fukumoto et al, 2002;Li et al, 2004;Yang et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Devi

Ohno

2011

Neuropsychopharmacol

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251

188

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Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer's disease (AD). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the b-secretase enzyme (BACE1) that initiates amyloid-b (Ab) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the b-secretasecleaved C-terminal fragment of amyloid precursor protein (C99), Ab40, and Ab42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and b-amyloidogenesis.

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“…the ability to calculate, and use common objects and tools. 9 The current symptomatic treatment of patients with mild to moderate AD is based on drugs such as donepezil, rivastigmine, galantamine and memantine which are associated with side effects. 10 These drugs may help keep symptoms from getting worse for a limited time.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of Picrorhiza kurroa on Alzheimer’s disease induced by aluminium chloride in rats

Reddy¹,

Sudheer²,

Arunamma³

et al. 2017

Int J Basic Clin Pharmacol

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Background: Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive deterioration together with declining activities of daily living and behavioural changes. The present work is aimed to investigate the effect of methanolic extract of rhizomes of Picrorhiza kurroa against aluminum chloride induced Alzheimer’s disease.Methods: Wistar rats were selected in this study and were divided into 5 groups (6 each). Group I served as normal control. Group II received aluminum chloride (300mg/kg, P.O.). Group III and IV received ethanolic extract of Picrorhiza kurroa (200mg/kg, 400mg/kg, P.O. respectively) and inducing agent (AlCl3 300mg/kg, P.O.). Group V received rivastigmine (0.3mg/kg, I.P.) and inducing agent (AlCl3 300mg/kg, P.O.). The rats were given respective treatment for 20 days and behavioural parameters were determined on 20th day. After 20th day rats were sacrificed and anti-oxidant parameters, brain acetylcholinesterase content were determined.Results: Oral administration of ethanolic extract of Picrorhiza kurroa at doses 200, 400mg/kg body weight showed improve in behavioural parameters when compared to AlCl3 induced rats, showed increase in superoxide dismutase, catalase, reduced glutathione and decreased levels of malondialdehyde and showed decrease in brain acetylcholinesterase content when compared to AlCl3 induced rats.Conclusions: The study clearly demonstrated the beneficial effects of Picrorhiza kurroa by improving biochemical and behavioural parameters.

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Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model

Cited by 273 publications

References 52 publications

7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Protective effect of Picrorhiza kurroa on Alzheimer’s disease induced by aluminium chloride in rats

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