TrkB activation by 7, 8‐dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease

Abstract

We recently demonstrated that activation of tyrosine receptor kinase B (TrkB) by 7, 8-dihydroxyflavone (7,, the selective TrkB agonist, increased surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPARs) AMPA receptor subunit GluR1 (GluA1) subunit expression at the synapses of Fragile X Syndrome mutant mice. This present study investigated the effects of 7, 8-DHF on both memory function and synapse structure in relation to the synapse protein level of AMPARs in the Tg2576 Alzheimer's disease (AD) mouse model. The study found that chronic oral administration of 7, 8-DHF significantly improved spatial memory and minimized dendrite loss in the hippocampus of Tg2576 mice. A key feature of 7, 8-DHF action was the increased expression of both GluA1 and GluA2 at synapses. Interestingly, 7, 8-DHF had no effect on the attenuation of amyloid precursor protein or Ab exhibiting in the Tg2576 AD brains, yet it activated the phosphorylation of TrkB receptors and its downstream signals including CaMKII, Akt, Erk1/2, and cAMP-response element-binding protein. Importantly, cyclotraxin B (a TrkB inhibitor), U0126 (a Ras-ERK pathway inhibitor), Wortmannin (an Akt phosphorylation inhibitor), and KN-93 (a CaMKII inhibitor) counteracted the enhanced expression and phosphorylation of AMPAR subunits induced by 7, 8-DHF. Collectively, our results demonstrated that 7, 8-DHF acted on TrkB and resolved learning and memory impairments in the absence of reduced amyloid in amyloid precursor protein transgenic mice partially through improved synaptic structure and enhanced synaptic AMPARs. The findings suggest that the application of 7, 8-DHF may be a promising new approach to improve cognitive abilities in AD.

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

“…The upregulation of ABCA1 by IL-17A was blocked by U0126, an ERK inhibitor. The ERK1/2 signaling pathway also participates in the spatial memory (Gao et al , 2016; Ghasemi et al , 2014; Liu et al , 2014). Thus, IL-17A overexpression may reduce CAA and soluble Aβ in the CSF and hippocampus by upregulating ABCA1 through the ERK1/2 signaling pathway.…”

A Christianson syndrome-linked deletion mutation (∆287ES288) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death

“…These analyses provide a framework for future investigations of other NHE6 mutations and potential avenues for therapeutic interventions aimed at modulating the trafficking of NHE6-dependent recycling endosomal cargo, such as TrkB and AMPAR, thereby mitigating cell dysfunction and damage in CS. These findings may also be relevant to our understanding of other neurodevelopmental or neurodegenerative disorders such as autism [119–123], fragile X syndrome [124, 125] and Alzheimer’s disease [126] where aberrations in recycling endosomal-associated cargo and signaling events have been implicated as contributing factors.…”

7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

“…It preserved integration of synapses and synaptic plasticity (Zeng et al, 2012), protects neurons from toxicity of β-amyloidogenesis as well as reduces expression of BACE1 in five familial AD mutation mouse model of AD (Devi and Ohno, 2012). It could also ameliorate spatial memory deficits via increasing synapse protein level of AMPA subunits even in the absence of attenuating expression of amyloid precursor protein or Aβ in the Tg2576 AD mouse model (Gao et al, 2016). Besides AD-associated memory impairment, 7,8-DHF could also reverse memory deficits in schizophrenia (Yang et al, 2014), Fragile x syndrome (Tian et al, 2015), scopolamine-induced memory dysfunction (Chen et al, 2014), and age-related cognitive impairment (Zeng et al, 2012).…”

“…The second group was cognitive impairment model group with 10 ApoE-KO mice in it. The third group was intervention group in which ApoE-KO mice were treated with 7,8-DHF chronically at the dose of 5 mg/kg (Devi and Ohno, 2012; Zeng et al, 2012; Gao et al, 2016) daily by oral administration for 25 weeks while the mice in other two groups were given vehicles daily. During the experiment, all the mice were measured weight and monitor health status every week.…”

“…As a consequence of activating TrkB, 7,8-DHF inhibits obesity in female mice (Chan et al, 2015), reduces spine morphology abnormalities in fragile X syndrome (Tian et al, 2015), enhances axon regeneration and muscle renovation after peripheral nerves injuries (English et al, 2013), improves motor function and prolongs survival in Huntington’s disease (Jiang et al, 2013). Furthermore, it can reverse synapse loss and prevent memory deficits in Alzheimer’s disease (AD; Zhang et al, 2014a; Gao et al, 2016). …”