Evaluating the Role of N-Acetyl-L-Tryptophan in the Aß 1-42-Induced Neuroinflammation and Cognitive Decline in Alzheimer's Disease.

Alzheimer's disease (AD), a neurodegenerative condition previously known to affect the older population, is also now seen in younger individuals. AD is often associated with cognitive decline and neuroinflammation elevation primarily due to amyloid ß (Aß) accumulation. Multiple pathological complications in AD call for therapies with a wide range of neuroprotection. Our study aims to evaluate the effect of N-acetyl-L-tryptophan (NAT) in ameliorating the cognitive decline and neuroinflammation induced by Aß 1-42 oligomers and to determine the therapeutic concentration of NAT in the brain. We administered Aß 1-42 oligomers in rats via intracerebroventricular (i.c.v.) injection to induce AD-like conditions. The NAT-treated animals lowered the cognitive decline in the Morris water maze characterized by shorter escape latency and increased path efficiency and platform entries. Interestingly, the hippocampus and frontal cortex showed downregulation of tumor necrosis factor, interleukin-6, and substance P levels. NAT treatment also reduced acetylcholinesterase activity and total and phosphorylated nuclear factor kappa B and Tau levels. Lastly, we observed upregulation of cAMP response element-binding protein 1 (CREB1) signaling. Surprisingly, our HPLC method was not sensitive enough to detect the therapeutic levels of NAT in the brain, possibly due to NAT concentrations being below the lowest limit of quantification of our validated method. To summarize, the administration of NAT significantly lowered cognitive decline, neuroinflammatory pathways, and Tau protein and triggered the upregulation of CREB1 signaling, suggesting its neuroprotective role in AD-like conditions.

Repressor Element-1 Binding Transcription Factor (REST) as a Possible Epigenetic Regulator of Neurodegeneration and MicroRNA-Based Therapeutic Strategies.

Neurodegenerative disorders (NDD) have grabbed significant scientific consideration due to their fast increase in prevalence worldwide. The specific pathophysiology of the disease and the amazing changes in the brain that take place as it advances are still the top issues of contemporary research. Transcription factors play a decisive role in integrating various signal transduction pathways to ensure homeostasis. Disruptions in the regulation of transcription can result in various pathologies, including NDD. Numerous microRNAs and epigenetic transcription factors have emerged as candidates for determining the precise etiology of NDD. Consequently, understanding by what means transcription factors are regulated and how the deregulation of transcription factors contributes to neurological dysfunction is important to the therapeutic targeting of pathways that they modulate. RE1-silencing transcription factor (REST) also named neuron-restrictive silencer factor (NRSF) has been studied in the pathophysiology of NDD. REST was realized to be a part of a neuroprotective element with the ability to be tuned and influenced by numerous microRNAs, such as microRNAs 124, 132, and 9 implicated in NDD. This article looks at the role of REST and the influence of various microRNAs in controlling REST function in the progression of Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) disease. Furthermore, to therapeutically exploit the possibility of targeting various microRNAs, we bring forth an overview of drug-delivery systems to modulate the microRNAs regulating REST in NDD.

Astrocytic MicroRNAs and Transcription Factors in Alzheimer's Disease and Therapeutic Interventions.

Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte-neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer's disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles.