Microglia, as immune cells in the central nervous system, are closely related to cognitive impairment associated with type 2 diabetes (T2D). Preliminary explorations have investigated the relationship between T2D-related cognitive impairment and the activation and polarization of microglia. This review summarizes the potential mechanisms of microglial activation and polarization in the context of T2D. It discusses central inflammatory responses, neuronal apoptosis, amyloid-β deposition, and abnormal phosphorylation of Tau protein mediated by microglial activation and polarization, exploring the connections between microglial activation and polarization and T2D-related cognitive impairment from multiple perspectives. Additionally, this review provides references for future treatment targeting microglia in T2D-related cognitive impairment and for clinical translation.

Alzheimer\'s disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer\'s disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.

In recent years, significant advancements have been made in understanding Alzheimer\'s disease from both neurobiological and clinical perspectives. Exploring the complex systems underlying AD has unveiled insights that could potentially revolutionize therapeutic approaches. Recent investigations have highlighted intricate interactions among genetic, molecular, and environmental factors in AD. Optimism arises from neurobiological advancements and diverse treatment options, potentially slowing or halting disease progression. Amyloid-beta plaques and tau protein tangles crucially influence AD onset and progression. Emerging treatments involve diverse strategies, such as approaches targeting multiple pathways involved in AD pathogenesis, such as inflammation, oxidative stress, and synaptic dysfunction pathways. Clinical trials using humanized monoclonal antibodies, focusing on immunotherapies eliminating amyloid-beta, have shown promise. Nonpharmacological interventions such as light therapy, electrical stimulation, cognitive training, physical activity, and dietary changes have drawn attention for their potential to slow cognitive aging and enhance brain health. Precision medicine, which involves tailoring therapies to individual genetic and molecular profiles, has gained traction. Ongoing research and interdisciplinary collaboration are expected to yield more effective treatments.

Tau protein aggregation is a defining characteristic of Alzheimer\'s disease (AD), leading to the formation of neurofibrillary tangles that disrupt neural communication and ultimately result in cognitive decline. Nanotechnology presents novel strategies for both diagnosing and treating Alzheimer\'s disease. Nanotechnology. It has become a revolutionary tool in the fight against Alzheimer\'s disease, particularly in addressing the pathological accumulation of tau protein. This review explores the relationship between tau-related neurophysiology and the utilization of nanotechnology for AD treatment, focusing on the application of nanomaterials to regulate tau phosphorylation, hinder tau aggregation and propagation, stabilize microtubules, eliminate pathological tau and emphasize the potential of nanotechnology in developing personalized therapies and monitoring treatment responses in AD patients. This review combines tau-related neurophysiology with nanotechnology to provide new insights for further understanding and treating Alzheimer\'s disease.

Aging is the main risk for neurodegenerative disorders like Alzheimer\'s disease. In this short review, I will comment on how delaying brain aging through the addition of Yamanaka Factors or small compounds that bind to the folate receptor alpha, which promote the expression of the Yamanaka Factors or by the decrease tau levels in brain cells from older subjects could serve as strategies to prevent Alzheimer\'s disease.

Abnormal deposition or aggregation of protein alpha-synuclein and tau in the brain leads to neurodegenerative disorders. Excessive hyperphosphorylation of tau protein and aggregations destroys the microtubule structure resulting in neurofibrillary tangles in neurons and affecting cytoskeleton structure, mitochondrial axonal transport, and loss of synapses in neuronal cells. Tau tubulin kinase 1 (TTBK1), a specific neuronal kinase is a potential therapeutic target for neurodegenerative disorders as it is involved in hyperphosphorylation and aggregation of tau protein. TTBK inhibitors are now the subject of intense study, but limited numbers are found. Hence, this study involves structure-based virtual screening of TTBK1 inhibitor analogs to obtain efficient compounds targeting the TTBK1 using docking, molecular dynamics simulation and protein-ligand interaction profile. The initial analogs set containing 3884 compounds was subjected to Lipinski rule and the non-violated compounds were selected. Docking analysis was done on 2772 compounds through Autodock vina and Autodock 4.2. Data Warrior and SwissADME was utilized to filter the toxic compounds. The stability and protein-ligand interaction of the docked complex was analyzed through Gromacs and VMD. Molecular simulation results such as RMSD, Rg, and hydrogen bond interaction along with pharmacokinetic properties showed CID70794974 as the potential hit targeting TTBKl prompting the need for further experimental investigation to evaluate their potential therapeutic efficacy in Alzheimer\'s disease.
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UNASSIGNED: The online version contains supplementary material available at 10.1007/s40203-024-00242-z.

Traumatic brain injury (TBI) stands as a significant contributor to traumatic death and disability worldwide. In recent years, researchers have identified biomarkers to gauge useful outcomes in TBI patients. However, the enigma of timely sample collection to measure the biomarkers remains a controversial point in the case of TBI, unlike other degenerative diseases like Alzheimer\'s disease and Parkinson\'s disease, where we can collect the sample at any point in time. The purpose of this study is to evaluate the sensitivity of biomarkers in TBI concerning time of injury by analyzing recent available data on biomarkers in the medical literature. A total of 2,256 studies were initially retrieved from the search engine. After an initial screening, only 1,750 unique articles remained. After excluding review articles, animal studies, meta-analysis, and studies with children (screened by title and abstract), 30 kinds of literature were found relevant to search the required variables. Further 16 studies were excluded due to the nonavailability of complete variables or data. Finally, 14 studies remained and were included in the analysis. This study has analyzed the four most commonly described biomarkers for TBI in the literature: glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B, ubiquitin carboxy-terminal hydrolase L1, and Tau. According to this statistical analysis, all biomarkers included in the study have shown their serum levels after trauma. So, all these biomarkers can be used for further study in the outcome prediction and diagnosis of TBI patients. The meta-analysis suggests that the best biomarker for TBI is Tau in cases where sample collection is done within 24 hours, while GFAP is the best biomarker to be studied for TBI if sample collection is done 24 hours after trauma.

Neuronal cell demise represents a prevalent occurrence throughout the advancement of Alzheimer\'s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Its potential mechanisms include aggregation of soluble amyloid-beta (Aβ) to form insoluble amyloid plaques, abnormal phosphorylation of tau protein and formation of intracellular neurofibrillary tangles (NFTs), neuroinflammation, ferroptosis, oxidative stress, liquid-liquid phase separation (LLPS) and metal ion disorders. Among them, ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. The sensitivity to ferroptosis is tightly linked to numerous biological processes. Moreover, emerging evidences indicate that LLPS has great impacts on regulating human health and diseases, especially AD. Soluble Aβ can undergo LLPS to form liquid-like droplets, which can lead to the formation of insoluble amyloid plaques. Meanwhile, tau has a high propensity to condensate via the mechanism of LLPS, which can lead to the formation of NFTs. In this review, we summarize the most recent advancements pertaining to LLPS and ferroptosis in AD. Our primary focus is on expounding the influence of Aβ, tau protein, iron ions, and lipid oxidation on the intricate mechanisms underlying ferroptosis and LLPS within the domain of AD pathology. Additionally, we delve into the intricate cross-interactions that occur between LLPS and ferroptosis in the context of AD. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for AD.

Intracellular tau aggregation requires a local protein concentration increase, referred to as \"droplets\". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer\'s disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.

Serotonin 5-HT7 receptors (5-HT7R) are attracting increasing attention as important participants in the mechanisms of Alzheimer\'s disease and as a possible target for the treatment of various tau pathologies. In this study, we investigated the effects of amisulpride (5-HT7R inverse agonist) in C57BL/6J mice with experimentally induced expression of the gene encoding the aggregation-prone human Tau[R406W] protein in the prefrontal cortex. In these animals we examined short-term memory and the expression of genes involved in the development of tauopathy (Htr7 and Cdk5), as well as biomarkers of neurodegenerative processes - the Bdnf gene and its receptors TrkB (the Ntrk2 gene) and p75NTR (the Ngfr gene). In a short-term memory test, there was no difference in the discrimination index between mice treated with AAV-Tau[R406W] and mice treated with AAV-EGFP. Amisulpride did not affect this parameter. Administration of AAV-Tau[R406W] resulted in increased expression of the Htr7, Htr1a, and Cdk5 genes in the prefrontal cortex compared to AAV-EGFP animals. At the same time, amisulpride at the dose of 10 mg/kg in animals from the AAV-Tau[R406W] group caused a decrease in the Htr7, Htr1a genes mRNA levels compared to animals from the AAV-Tau[R406W] group treated with saline. A decrease in the expression of the Bdnf and Ntrk2 genes in the prefrontal cortex was revealed after administration of AAV-Tau[R406W]. Moreover, amisulpride at various doses (3 and 10 mg/kg) caused the same decrease in the transcription of these genes in mice without tauopathy. It is also interesting that in mice of the AAV-EGFP group, administration of amisulpride at the dose of 10 mg/kg increased the Ngfr gene mRNA level. The data obtained allow us to propose the use of amisulpride in restoring normal tau protein function. However, it should be noted that prolonged administration may result in adverse effects such as an increase in Ngfr expression and a decrease in Bdnf and Ntrk2 expression, which is probably indicative of an increase in neurodegenerative processes.
Серотониновые рецепторы 5-HT7 (5-HT7R) привлекают все больше внимания в качестве одного из важных звеньев в механизмах развития болезни Альцгеймера и возможной мишени для лечения различных тау-патологий. В настоящей работе исследовано влияние амисульприда (обратный агонист 5-HT7R) в модели экспериментального повышения экспрессии гена, кодирующего склонный к агрегации белок человека Tau[R406W], в префронтальной коре мышей линии C57BL/6J на кратковременную память и экспрессию генов, участвующих в развитии таупатии (Htr7 и Cdk5), а также биомаркеров нейродегенеративных процессов – гена Bdnf и его рецепторов TrkB (ген Ntrk2) и p75NTR (ген Ngfr). В тесте на кратковременную память мыши не было обнаружено разницы по индексу дискриминации между мышами, которым вводили AAV-Tau[R406W], и мышами с AAV-EGFP. Амисульприд не повлиял на данный показатель. Введение AAV-Tau[R406W] привело к повышению экспрессии генов Htr7, Htr1a и Cdk5 в префронтальной коре по сравнению с животными группы AAV-EGFP. При этом амисульприд в дозе 10 мг/кг у животных группы AAV-Tau[R406W] вызвал снижение уровня мРНК генов Htr7 и Htr1a по сравнению с животными группы AAV-Tau[R406W], которым вводили физиологический раствор. Выявлено снижение экспрессии генов Bdnf и Ntrk2 в префронтальной коре после введения AAV-Tau[R406W]. При этом амисульприд в различных дозах (3 и 10 мг/кг) вызывал такое же снижение транскрипции этих генов у мышей без таупатии. Интересно также, что у мышей группы AAV-EGFP после введения амисульприда в дозе 10 мг/кг повышался уровень мРНК гена Ngfr. Полученные данные позволяют рассматривать амисульприд в качестве агента для восстановления нормальной функции тау-белка. Однако следует учитывать возможный негативный эффект амисульприда при длительном применении, отражающийся в увеличении экспрессии гена Ngfr и снижении экспрессии генов Bdnf и Ntrk2, что может указывать на усиление нейродегенеративных процессов.