Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease

Bello-Medina, Paola C.; González-Franco, Diego A.; Vargas‐Rodríguez, Isaac; Dı́az-Cintra, Sofı́a

doi:10.1016/j.nrleng.2019.06.008

Cited by 14 publications

(10 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…More importantly, a downregulation of the K V 2.1-mediated currents might be expected to have a crucial impact on hippocampal and cortical excitability in the Tg2576 mouse. In this regard, a previous study by Frazzini and colleagues [ 43 ] revealed that the reduction in the K V 2.1 current density due to channel oxidation was associated with the spontaneous hyperexcitability observed in the neurons from the 3xTg-AD mouse, a transgenic model characterized by elevated levels of oxidative stress in the early phases of the pathology [ 67 ]. In particular, they observed increased [Ca 2+ ] i spike frequency in the 3xTg-AD neurons, where the K V 2.1-mediated currents were downregulated, and obtained similar results in the non-transgenic neurons upon the pharmacological blockade of K V 2.1 [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Increased KV2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K+ Currents in Hippocampal Neurons of the Tg2576 Alzheimer’s Disease Mouse

Piccialli

Sisalli

Rosa

et al. 2022

Cells

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Cortical and hippocampal hyperexcitability intervenes in the pathological derangement of brain activity leading to cognitive decline. As key regulators of neuronal excitability, the voltage-gated K+ channels (KV) might play a crucial role in the AD pathophysiology. Among them, the KV2.1 channel, the main α subunit mediating the delayed rectifier K+ currents (IDR) and controlling the intrinsic excitability of pyramidal neurons, has been poorly examined in AD. In the present study, we investigated the KV2.1 protein expression and activity in hippocampal neurons from the Tg2576 mouse, a widely used transgenic model of AD. To this aim we performed whole-cell patch-clamp recordings, Western blotting, and immunofluorescence analyses. Our Western blotting results reveal that KV2.1 was overexpressed in the hippocampus of 3-month-old Tg2576 mice and in primary hippocampal neurons from Tg2576 mouse embryos compared with the WT counterparts. Electrophysiological experiments unveiled that the whole IDR were reduced in the Tg2576 primary neurons compared with the WT neurons, and that this reduction was due to the loss of the KV2.1 current component. Moreover, we found that the reduction of the KV2.1-mediated currents was due to increased channel clustering, and that glutamate, a stimulus inducing KV2.1 declustering, was able to restore the IDR to levels comparable to those of the WT neurons. These findings add new information about the dysregulation of ionic homeostasis in the Tg2576 AD mouse model and identify KV2.1 as a possible player in the AD-related alterations of neuronal excitability.

show abstract

Section: Discussionmentioning

confidence: 99%

Increased KV2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K+ Currents in Hippocampal Neurons of the Tg2576 Alzheimer’s Disease Mouse

Piccialli

Sisalli

Rosa

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…The magnitude and dynamics of neuroplastic changes are determined by genetic, epigenetic, and environmental factors and change with age. Changes in synaptic plasticity in brain structures, such as the hippocampus, amygdala, striatum, and cortex, have a determining role in learning and memory processes, which are cognitive processes are impaired in AD [ 14 , 232 , 237 , 238 ]. The history of the concept of neuroplasticity, which relates to the understanding of AD, was previously reviewed by Teter and Ashford [ 239 ].…”

Section: Hypotheses Of Alzheimer’s Diseasementioning

confidence: 99%

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Fišar

2022

Biomolecules

View full text Add to dashboard Cite

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

show abstract

“…Some authors described that the abnormal accumulation of Aβ and the deposition of neurofibrillary tangles extend oxidative damage, impair Ca 2+ homeostasis and produce mitochondrial dysfunction during AD ( Bello-Medina et al, 2021 ). Nevertheless, other studies claim that during AD the increased ROS production and altered Ca 2+ homeostasis precede Aβ accumulation and is due to mitochondrial dysfunction ( Yoo et al, 2020 ).…”

Section: Microglial Activation In Alzheimer’s Diseasementioning

confidence: 99%

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Revuelta

Urrutia

Villarroel

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer’s Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1β and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.

show abstract

Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease

Cited by 14 publications

References 81 publications

Increased KV2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K+ Currents in Hippocampal Neurons of the Tg2576 Alzheimer’s Disease Mouse

Increased KV2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K+ Currents in Hippocampal Neurons of the Tg2576 Alzheimer’s Disease Mouse

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Contact Info

Product

Resources

About