Much of the research on Alzheimer's disease (AD) has focused on amyloid (A) and its accumulation, and relatively few studies have been conducted on the interaction between A and ion channels. An interesting study published in Scientific Reports revealed a strong association between a specific type of voltage-gated sodium channel (n**) and neuronal overactivation in Alzheimer's disease. This study not only sheds new light on the role of n** pathways, but also opens up a promising avenue for potential interventions that could help fight Alzheimer's disease (AD) in its early stages.
a and n**16. What is the connection?
In their search for answers, the research team shifted their focus to voltage-gated sodium channels. These channels are closely associated with the overactivity of hippocampal neurons in Alzheimer's disease (AD) and the rise in seizure frequency. Using primitive hippocampal neurons exposed to amyloid-1-42 (A 1-42) oligomers, a hallmark of AD, the research team embarked on a research journey to unravel the mystery of neuronal overactivation. The research team used two unique in vitro experimental models to mimic amyloid pathology: one was treated with mouse hippocampal neuronal primary cultures for 24 hours by synthesizing A1-42 oligomers, and the other was primary cultures of mouse hippocampal neurons with TG2576. This primary culture is capable of endogenously producing peptide A1-42 and accumulating in the culture over time. They also employed the sodium channel blocker tetrodotoxin citrate (TTX) (T-550) to interrupt the current from endogenous N**.
After exposing hippocampal neurons to A1-42, use anti-N**16 (SCN8A) antibody (ASC-009) was blotted at Western. Experimental results show that these A1-42 oligomers begin to accumulate after 24 h and selectively increase n**1Expression and activity of 6 channels (see Figure 1). The research team also used anti-SCN1A (n**1.).1) Antibody (ASC-001) and anti-SCA2A (N**1.)2) antibodies (ASC-002) to study the expression of these proteins in the presence of A1-42. They observed that n**16 Selective upregulation plays a key role in membrane depolarization and the rise in spike frequency, which is the main cause of neuronal death.
To validate their findings, the research team selected TG2576 mouse embryos as a mouse model to study Alzheimer's disease. The researchers observed that hippocampal neurons extracted from these mice exhibited n**16 channels are up-regulated, but to n**11 and n**1There was no significant effect on the 2 channels, while the spike frequency, membrane depolarization, and current density also showed an upward trend.
These studies are as follows: a1-42 oligomers and n**1A critical link was established between the 6 channels, consolidating the function of the channel in the event of hyperactivation of hippocampal neurons.
When exposed to A1-42, n**1 in primary cultured hippocampal neurons6. The activity and expression levels of proteins will be selectively upregulated.
Figure 1Effect of exposure to A1-42 at 10-12div on Na+ currents in primary hippocampal neurons. (a) under control conditions, as well as in 0After 24 h of exposure to 1 m, 1 m, and 5 m A 1-42, representative trajectories of Na+ currents in primary hippocampal neurons were recorded. (b) under control conditions, as well as at 0Normalization of NA+ current density recorded at -20 mV in primary hippocampal neurons after 24 h of action at 1 m, 1 m, 5 mA 1-42, and 5 m A 42-1. The number of cells used for each experimental condition is noted on the bar graph, and the numeric value is expressed as the average percentage SEM for 3 independent experiments. Compared to the control group, *p 005；Compared to the control group, *p 0001；Compared to 01μm，^p＜0.05；Compared to 01 and 1 m, p 0001。(c) Normalization of NA+ current density at -20 mV recorded by primary hippocampal neurons under control conditions and after 1 h, 12 h, 24 h, and 48 h of action at 5 M A 1-42. The number of cells used in each experimental condition is noted on the bar graph, and the values are expressed as a percentage of the average SEM of the 3 independent experiments. Compared to the control group, **p < 0001；Compared to 1 hour, p < 0001；Compared to 1 hour and 12 hours, p < 0001；Compared to 24 hours, p < 0001。(d) Representative galographygrams of primary hippocampal neurons recorded in gapless mode under control group conditions and after 5 M A 1-42 (24 h). (e) Quantitative analysis of the effect of a1-42 on spike frequency under control conditions and after 5 M a 1-42 (24 h) in primary hippocampal neurons. The number of cells used for each experimental condition is noted on a bar graph, and the values are expressed as the average percentage SEM of the 3 independent experiments. Compared to the control group, **p < 0001。(f) Quantitative analysis of the effect of primary hippocampal neurons on membrane potential under control conditions and after 5 M a 1-42 (24 h). The number of cells used for each experimental condition is noted on a bar graph, and the values are expressed as the average percentage SEM of the 3 independent experiments. Compared to the control group, **p < 0001。Excerpted from Ciccone, R et al. sci rep9, 13592 (2019)。
n**1.6 Expression and silence.
Whereas, a 1-42 is the same as n**16 The association has been revealed, and the research team has conducted an in-depth acting on its mechanism of action and studied n**16 roles in A1-42-induced neuronal excitability. To achieve this, they adopted n**16 siRNA and anisemycin were treated in an attempt to reverse the electrophysiological changes.
Both techniques significantly reduced the Na+ current in the hippocampus of the TG2576 mice, effectively inhibiting changes in electrophysiology (e.g., increased spike frequency and membrane depolarization), and even reducing the amplitude and frequency of spontaneous action potentials.
To gain insight into the expression in the mouse model, the research team used anti-n**16-channel (ASC-009) and anti-microtubule-associated protein (MAP2) to dual-label tissue neurons. Here, they observed that N**1 was found to be superior to WT neurons (Figure 2A-C).6 Punctate staining was shown in the neural medulla and somite portions of WT hippocampal neurons (Figure 2A), while perimedullary staining was evident in the TG2576 hippocampal neurons (Fig. 2A, D-F) sections. They also observed that aniticin successfully reversed N**1 in TG2576 hippocampal neurons6 Rise in immune activity (see Figure 2Ag-I).
These results confirm n**1The 6-channel has a specific role in the process of a1-42-triggered neuronal overactivation.
Anisomycin treatment reduces n**1 in TG2576 hippocampal neurons6. Growth of the immune response.
In Figure 2At 12 div, TG2576 primary hippocampal neurons were treated with isomycin, n**16. Immunocytochemical analysis of protein expression (anti-n**1.)6（scn8a）#asc-009）。(A) Immunofluorescence confocal image showing wt(a-c) and tg2576 primary hippocampal neurons in the absence of (d-f) or with (g-i) aniticin n**1Distribution of 6 (green) and MAP2 (red). Scale in A-I: 20 m. (B) Quantitative analysis: WT and TG2576 primary hippocampal neurons in the presence and absence of anisemycin in the ventricle n**16 positive points. Ruler: 5 m. Data are presented as average SEMs of 20 cells in each group over 3 independent experiments. Compared to WT, **p 001；Compared to TG2576, the value of p is 0001。Excerpted from Ciccone, R et al. sci rep9, 13592 (2019)。
Solve the mystery. As the puzzle progressively completed, the research team began to explore how oligomers a1-42 enhance n**1 in hippocampal neurons6 of the active. They observed that due to A1-42 oligomers and intracellular accumulation, n**16. Protein expression and functional activity, selectivity were improved. Interestingly, this upregulation was also observed in TG2576 hippocampal neurons, which further strengthened the relationship between A1-42 and N**16 channels of interconnection.
Although there is a lot of talk about how A1-42 oligomers enhance N**1The specific mechanism of 6 activity is not well understood, but the researchers speculate that it may involve alterations in gene transcription, reduced protein degradation, or interactions of A1-42 with other proteins such as amyloid precursor proteins (APPs), which may affect N**16 channels are transferred to the location of the cell membrane.
About n**16 and the unsolved mystery of AD.
Despite the curiosity of the research landscape, there are still unsolved mysteries and challenges that need to be addressed. The research team has presented convincing evidence that suggests n**16 is associated with overexcitability of neurons in the context of Alzheimer's disease (AD). Nonetheless, A1-42 oligomers increase n**16. The mechanism of action of activity is still unknown. Understanding these mechanisms is critical to the development of targeted** drugs.
The interaction between a 1-42 oligomers and the ubiquitin system responsible for protein degradation is a compelling topic. Observations have shown that A1-42 oligomers are able to disrupt the ubiquitin system, resulting in reduced protein degradation in mouse models of Alzheimer's disease (AD). Whether this imbalance can lead to n**1An upward adjustment of 6? Delving into the complex relationships between **A 1-42 and the ubiquitin system may reveal more ** targets.
Although this study mainly focuses on n**16 plays a role in neuronal overactivation, but its potential impact may be more extensive. As we learn more about the complexities of Alzheimer's disease (AD), **n**16 Whether it contributes to the development of synaptic dysfunction, neuroinflammation and other related diseases becomes critical. This knowledge has the potential to provide entirely new avenues for interventions.
n**1.6: An important new character.
This study reveals not only n**1The function of the 6 channels in Alzheimer's disease (AD) disease also provides us with possible methods. Researchers are theoretically able to target n**1Upregulation and activation of 6 channels to combat hyperexcitability and subsequent cognitive impairment in the hippocampus in the early stages of Alzheimer's disease (AD).
It is worth emphasizing that the application of these findings to clinical practice is a challenging task. Development of specific targeting n**16 Drugs, while avoiding off-target effects, have been a problem that drug development scientists around the world have struggled to solve, and the potential benefits are enormous.
The implications of this study go far beyond Alzheimer's disease (AD). Hyperexcitability and disturbance of the neuronal network are also characteristic of other neurological disorders such as epilepsy. Learn more about n**16 The role of these diseases could have even more profound implications for neuroscience.
Taken together, this study brings us one step closer to understanding the complex workings of the brain in Alzheimer's disease (AD). Scientists have made this work by revealing n**16 The central role in neuronal overactivation initiated by oligomers 1-42 provides a promising target for the future. Although there is still a great deal of research to be done, these new findings provide a new direction for Alzheimer's disease (AD) and other neurological-related diseases, and ensure the centrality of ion channels in research.
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Related Literature: ciccone r, franco c, piccialli i, boscia f, casamassa a, de rosa v, cepparulo p, cataldi m, annunziato l, pannaccione a. amyloid β-induced upregulation of n**1.6 underlies neuronal hyperactivity in tg2576 alzheimer's disease mouse model. sci rep. 2019 sep 19;9(1):13592. doi: 10.1038/s41598-019-50018-1. pmid: 31537873; pmcid: pmc6753212.