Soluble β-amyloid impaired the GABA inhibition by mediating KCC2 in early APP/PS1 mice

Zhou, Yuan; Cheng, Yujie; Li, Yong; Ma, Jiyao; Wu, Zhihan; Chen, Yuenan; Mei, Jinyu; Chen, Ming

doi:10.5582/bst.2021.01245

Cited by 8 publications

(8 citation statements)

References 64 publications

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“…This shift is produced via TrkB activation and a decrease in the expression of K + -Cl − cotransporter KCC2 (Rivera et al, 2002;Ulmann et al, 2008;Trang et al, 2009). In AD models it has been observed a similar pattern, with decreased KCC2 expression, increased BDNF and TNF-α (Doshina et al, 2017;Zhou et al, 2021), which could link both pathologies related to aging and neuroinflammation.…”

Section: Increased Expression Of P2x4 Receptor On Microglial Cellsmentioning

confidence: 87%

Microglial Activation Modulated by P2X4R in Ischemia and Repercussions in Alzheimer’s Disease

et al. 2022

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There are over 80 million people currently living who have had a stroke. The ischemic injury in the brain starts a cascade of events that lead to neuronal death, inducing neurodegeneration which could lead to Alzheimer’s disease (AD). Cerebrovascular diseases have been suggested to contribute to AD neuropathological changes, including brain atrophy and accumulation of abnormal proteins such as amyloid beta (Aβ). In patients older than 60 years, the incidence of dementia a year after stroke was significantly increased. Nevertheless, the molecular links between stroke and dementia are not clearly understood but could be related to neuroinflammation. Considering that activated microglia has a central role, there are brain-resident innate immune cells and are about 10–15% of glial cells in the adult brain. Their phagocytic activity is essential for synaptic homeostasis in different areas, such as the hippocampus. These cells polarize into phenotypes or subtypes: the pro-inflammatory M1 phenotype, or the immunosuppressive M2 phenotype. Phenotype M1 is induced by classical activation, where microglia secrete a high level of pro- inflammatory factors which can cause damage to the surrounding neuronal cells. Otherwise, M2 phenotype is the major effector cell with the potential to counteract pro-inflammatory reactions and promote repair genes expression. Moreover, after the classical activation, an anti-inflammatory and a repair phase are initiated to achieve tissue homeostasis. Recently it has been described the concepts of homeostatic and reactive microglia and they had been related to major AD risk, linking to a multifunctional microglial response to Aβ plaques and pathophysiology markers related, such as intracellular increased calcium. The upregulation and increased activity of purinergic receptors activated by ADP/ATP, specially P2X4R, which has a high permeability to calcium and is mainly expressed in microglial cells, is observed in diseases related to neuroinflammation, such as neuropathic pain and stroke. Thus, P2X4R is associated with microglial activation. P2X4R activation drives microglia motility via the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Also, these receptors are involved in inflammatory-mediated prostaglandin E2 (PGE2) production and induce a secretion and increase the expression of BDNF and TNF-α which could be a link between pathologies related to aging and neuroinflammation.

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Section: Increased Expression Of P2x4 Receptor On Microglial Cellsmentioning

confidence: 87%

Microglial Activation Modulated by P2X4R in Ischemia and Repercussions in Alzheimer’s Disease

et al. 2022

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“…Imbalances between NKCC1 and KCC2 have recently been shown in patients with AD ( 77 , 78 ) that are exacerbated with the onset of epileptic activity, indicating that hyperexcitability can act as a feed-forward mechanism to promote excitatory GABAergic signaling. Previous findings in preclinical models of amyloid-beta deposition (APP/PS1 transgenic mice and Aβ 1-40 fibril treatment) note reduced KCC2 protein expression in the hippocampus and cortex ( 71 , 76 , 79 , 80 ) with increases in NKCC1 protein expression ( 81 ). One study, however, indicates increases in KCC2 in a different model of AD-related pathology.…”

Section: Alzheimer’s Disease and Dementiamentioning

confidence: 87%

“…Therefore, further exploration is required to definitively confirm the effects of Aβ plaque and different structural forms of Aβ on chloride homeostasis and excitatory GABAergic signaling. Interestingly, treatment with γ-secretase inhibitor, LY411575, restored KCC2 levels in APP/PS1 mice, highlighting the direct impact of Aβ plaque on KCC2 expression ( 80 ). Finally, in an APOE4-KI mouse, a model for the largest genetic risk factor of AD, also presents with an increased ratio between NKCC1 and KCC2 expression ( 83 ).…”

Section: Alzheimer’s Disease and Dementiamentioning

confidence: 99%

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders

McArdle,

Arnone,

Heaney

et al. 2024

Front. Psychiatry

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Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. In the mature brain, inhibitory GABAergic signaling is critical in maintaining neuronal homeostasis and vital human behaviors such as cognition, emotion, and motivation. While classically known to inhibit neuronal function under physiological conditions, previous research indicates a paradoxical switch from inhibitory to excitatory GABAergic signaling that is implicated in several neurological disorders. Various mechanisms have been proposed to contribute to the excitatory switch such as chloride ion dyshomeostasis, alterations in inhibitory receptor expression, and modifications in GABAergic synaptic plasticity. Of note, the hypothesized mechanisms underlying excitatory GABAergic signaling are highlighted in a number of neurodevelopmental, substance use, stress, and neurodegenerative disorders. Herein, we present an updated review discussing the presence of excitatory GABAergic signaling in various neurological disorders, and their potential contributions towards disease pathology.

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“…Extracellular Aβ deposition, a hallmark of AD pathogenesis, leads to network dysfunction through synaptic loss and neuronal degeneration, instigating the AD pathological cascade. 21 - 23 This is primarily facilitated by sequential proteolytic processing of the amyloid precursor protein (APP), a ubiquitous transmembrane protein known to be cleaved during subcellular trafficking when co-compartmentalized with active APP secretases. 24 Notably, Aβ production predominantly occurs at the Golgi apparatus and endosomes via active β- and γ-secretases, 25 where the rate-limiting step is BACE-1 cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…There is emerging evidence that APP can modulate the expression of KCC2 and hippocampal GABAergic inhibition in APP knock-out models. 10 , 22 Chronic exposure to Aβ42 has been shown to affect the expression of cation–chloride cotransporters (CCC), namely K-Cl-2 (KCC2) and N-K-Cl-1 (NKCC1), in the hippocampus of AD mice, potentially disrupting the balance of excitatory and inhibitory signals. 23 Additionally, 40 Hz gamma frequency light flickering may enhance KCC2 expression and PKC-dependent phosphorylation of APP on a serine residue.…”

Section: Discussionmentioning

confidence: 99%

White Light Stimulation at Gamma Frequency to Modify the Aβ42 and tau Proteins in SH-SY5Y Cells

Chang,

Chien,

Huang

et al. 2024

Am J Alzheimers Dis Other Demen

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Background Non-invasive 40 Hz gamma frequency stimulation has shown improved cognition and memory recall in Alzheimer’s disease (AD). Purpose The present study investigates the effects of white light stimulation at gamma frequency on SH-SY5Y cells using Delta M + BrainCare Light without causing discomfort. Methods SH-SY5Y cells were exposed to The Delta M + BrainCare Light for 15, 30, 45, and 60 minutes. The secretion of amyloid-β42 (Aβ42), p-AKT (Ser473), AKT, p-mTOR (Ser2448), mTOR, p-4E-BP1 (Thr37/46), 4E-BP1, p-tau (Thr181), and tau were analyzed. Aβ42 fibril aggregation and phagocytosis of FITC-Aβ42 in BV-2 cells were also observed. Results Delta M + BrainCare Light reduced tau, AKT, and p-mTOR and increased p-4E-BP1 in SH-SY5Y cells. Further, it inhibited secretion and aggregation of Aβ42, alongside increased phagocytosis in microglial cells. Conclusion These findings underscore the potential of the Delta M + BrainCare Light in mitigating the associated proteins and pathways implicated in AD.

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Soluble β-amyloid impaired the GABA inhibition by mediating KCC2 in early APP/PS1 mice

Cited by 8 publications

References 64 publications

Microglial Activation Modulated by P2X4R in Ischemia and Repercussions in Alzheimer’s Disease

Microglial Activation Modulated by P2X4R in Ischemia and Repercussions in Alzheimer’s Disease

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders

White Light Stimulation at Gamma Frequency to Modify the Aβ42 and tau Proteins in SH-SY5Y Cells

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