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An illustration of the mitochondrial dysfunction and oxidative stress in the pathogenesis of AD. (A) Multiple age-related processes, mutations, and toxic fluctuations such as metal exposure can all adversely affect mitochondria. Mitochondrial dysfunction further results in bioenergetic deficits, calcium imbalance, and free radical production. This causes oxidative stress, which exacerbates mitochondrial impairment, synaptic malfunction, cognitive decline, and memory loss. (B) The cellular redox equilibrium is disrupted by ROS generation or a compromised antioxidant arrangement, which leads to an oxidative imbalance and excessive ROS output. By adversely influencing mitochondrial energy reserves, disrupting energy metabolic processes, and impairing dynamics and mitophagy, elevated ROS reduces mitochondrial ΔΨm and ATP production. Caspase activity also rises as a result of ROS, which additionally starts the apoptotic process. However, excessive ROS generation inhibits phosphatase 2A (PP2A), which leads to glycogen synthase kinase 3 (GSK3) activation. This results in tau hyperphosphorylation and NFT buildup. (C) The functions of the mitochondria that are extensively hampered in AD have been highlighted.
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Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. The early stages of neurodegeneration in AD include the loss of n...
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... This disease was detected to be extracellular plaques formed by aggregation of amyloid beta protein and intracytoplasmic neurofibrillary tangles (NFTs) caused by hyperphosphorylation of tau protein impede synaptic transmission, activate inflammatory responses, and disrupt neuronal metabolism of amyloid plaques. Blocking synaptic transmission, activating inflammatory responses, disrupting neuronal metabolism, blockage of ion channels, disturbance of calcium homeostasis, mitochondrial oxidative stress, impaired energy metabolism, abnormal glucose regulation, altered synaptic function, and causing cell apoptosis are the results of accumulation of the Aβ amyloid protein [1]. The second hypothesis about AD is related to the ApoE apolipoprotein. ...
With the quick pace of the society, changing of the majority part of the population age distribution, and the aggravation of the population aging results in the gradual growth of Alzheimer disease (AD) patients’ percentage. Nowadays, researchers are still not totally clear about the etiology and pathogenesis of AD; nonetheless, two hypotheses have emerged: AB amyloid protein and ApoE4 apolipoprotein hypothesis. This paper aims to go through the introduction of ApoE4, then elaborate on the pathogenic mechanism of the ApoE4 hypothesis in AD disease, and finally analyze the new detection method of AD disease. Last but not least, determining whether people suffer from AD and the degree of AD disease through whether tau181 site phosphorylation. This paper provides minimal help for researchers to conduct deeper detection and research in the future. In the future, studying the exact pathogenesis of AD, more perfect AD detection protocols, and ways to treat different levels of AD will still be some of the main challenges that researchers will face when conducting more in-depth research in the field of AD.
The 10th Anniversary Special Issue of Biomedicines presents a collection of 21 pioneering papers focusing on Translational Laboratory and Experimental Medicine for Neurological Diseases and Mental Illnesses. This edition explores the complex interactions that occur within the human brain, including neuroplasticity, cognitive responses, and the influence of aging on behavior. Researchers and clinicians have dedicated themselves to unraveling the mysteries of brain function and mental health, proposing novel therapeutic approaches and potential advancements in the field. Through their investigations of neural circuits, plasticity, and brain adaptation, the papers in this special issue shed important light on the mechanisms that underlie mental illnesses and neurological disorders. From investigating the brain's ability to recover after a stroke to exploring the relationship between neural activity and cognitive function, this collection of papers showcases the relentless dedication and innovation in the field of biomedicine. As we commemorate a decade of pioneering research, these findings pave the way for future studies aimed at improving the lives of people living with neurological conditions and mental health challenges.
Alzheimer's disease (AD) research started several decades ago and despite the many efforts employed to develop new treatments or approaches to slow and/or revert disease progression, AD treatment remains an unsolved issue. Knowing that mitochondria loss of function is a central hub for many AD-associated pathophysiological processes, there has been renewed interest in exploring mitochondria as targets for intervention. In this perspective, the present study was aimed to investigate the possible beneficial effects of 2,4 dinitrophenol (DNP), a mitochondrial uncoupler agent, in an in vitro model of AD. Retinoic acid-induced differentiated SH-SY5Y cells were incubated with okadaic acid (OA), a neurotoxin often used as an AD experimental model, and/or with DNP. OA caused a decrease in neuronal cells viability, induced multiple mitochondrial anomalies including increased levels of reactive oxygen species, decreased bioenergetics and mitochondria content markers, and an altered mitochondria morphology. OA-treated cells also presented increased lipid peroxidation levels, and overactivation of tau related kinases (GSK3β, ERK1/2 and AMPK) alongside with a significant augment in tau protein phosphorylation levels. Interestingly, DNP co-treatment ameliorated and rescued OA-induced detrimental effects not only on mitochondria but also but also reinstated signaling pathways homeostasis and ameliorated tau pathology. Overall, our results show for the first time that DNP has the potential to preserve mitochondria homeostasis under a toxic insult, like OA exposure, as well as to reestablish cellular signaling homeostasis. These observations foster the idea that DNP, as a mitochondrial modulator, might represent a new avenue for treatment of AD.
Familial Alzheimer’s disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAβ; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (DYm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 μM), CU (10 μM), or SP (1 μM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 μM) concentration was efficient in diminishing the iAβ, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by −50%, −75%, −86%, and −100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by −69% and −38%, −100% and −62%, −100% and −62%, respectively, these combinations did not alter the iAβ compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAβ-induced ChLN damage in FAD.
This review provides a comprehensive examination of the role of clathrin-mediated endocytosis (CME) in Alzheimer’s disease (AD) pathogenesis, emphasizing its impact across various cellular contexts beyond neuronal dysfunction. In neurons, dysregulated CME contributes to synaptic dysfunction, amyloid beta (Aβ) processing, and Tau pathology, highlighting its involvement in early AD pathogenesis. Furthermore, CME alterations extend to non-neuronal cell types, including astrocytes and microglia, which play crucial roles in Aβ clearance and neuroinflammation. Dysregulated CME in these cells underscores its broader implications in AD pathophysiology. Despite significant progress, further research is needed to elucidate the precise mechanisms underlying CME dysregulation in AD and its therapeutic implications. Overall, understanding the complex interplay between CME and AD across diverse cell types holds promise for identifying novel therapeutic targets and interventions.
Background With few effective treatments, Alzheimer's disease (AD) represents a substantial worldwide health burden. Potential disease-modifying treatments have gained attention due to recent developments in immunotherapy that target TAU protein. The purpose of this thorough analysis is to investigate the safety and efficacy of TAU protein antibodies in the treatment of AD. Methodology This review investigates the safety and efficacy of TAU protein antibodies as possible treatments for AD. Using a variety of databases, a thorough literature search was carried out with an emphasis on clinical trials and academic publications regarding TAU protein antibodies in AD. Predetermined criteria were used to select eligible studies, and pertinent data were then retrieved and compiled. PRISMA guidelines for transparency were followed in the reporting. Conclusion TAU protein antibodies have shown some potential in trials for treating Alzheimer's disease, including a little improvement in cognitive deterioration. Safety considerations highlight the need for cautious interpretation, especially with regard to imaging abnormalities due to amyloid. Optimizing efficacy, safety, and cost-effectiveness requires further studies.
The leading pathological mechanisms of Alzheimer’s disease are amyloidosis and inflammation. The presented work was aimed to study the effect of human peripheral blood mononuclear cells (hPBMcs) cells-matrix adhesion on their pro-inflammatory state in vitro. Although direct interaction of Аβ42 to PBMC is not a cellular model of Alzheimer’s disease, PBMCs may serve as test cells to detect Аβ42-dependent molecular effects in monitoring disease progression. Peripheral blood mononuclear cells (PBMCs) are used to assess changes in cytokines released in response to diseases or Alzheimer’s disease-specific cytotoxic molecules such as Aβ42. The effect of recombinant amyloid β-peptide rАβ42 on the concentration of endogenous amyloid β-peptide Aβ40 and pro-inflammatory cytokines TNFα and IL-1β in human peripheral blood mononuclear cells that were cultured in suspension and immobilized in alginate microcarriers for 24 h were investigated. The localization and accumulation of Aβ40 and rAβ42 peptides in cells, as well as quantitative determination of the concentration of Aβ40 peptide, TNFα and IL-1β cytokines, was performed by intravital fluorescence imaging. The results were qualitatively similar for both cell models. It was determined that the content of TNFα and Aβ40 in the absence of rAβ42 in the incubation medium did not change for 24 h after incubation, and the content of IL-1β was lower compared to the cells that were not incubated. Incubation of cells in vitro with exogenous rAβ42 led to an increase in the intracellular content of TNFα and Aβ40, and no accumulation of IL-1β in cells was observed. The accumulation of Aβ40 in the cytoplasm was accompanied by the aggregation of rAβ42 on the outer surface of the cell plasma membrane. It was shown that the basic levels of indicators and the intensity of the response of immobilized cells to an exogenous stimulus were significantly greater than those of cells in suspension. To explore whether non-neuronal cells effects in alginate microcarriers were cell-matrix adhesion mediated, we tested the effect of blocking β1 integrins on proamyloidogenic and proinflammation cellular state. Immobilization within alginate hydrogels after incubation with the β1 integrins blocking antibodies showed a remarkable inhibition of TNFα and Aβ40 accumulation in rAβ42-treated cells. It can be concluded that activation of signal transduction and synthesizing activity of a portion of mononuclear cells of human peripheral blood is possible (can significantly increase) in the presence of cell-matrix adhesion.
Neuroinflammation is an important pathogenesis of neurological diseases and causes a series of physiopathological changes, such as abnormal activation of glial cells, neuronal degeneration and death, and disruption of the blood‒brain barrier. Therefore, modulating inflammation may be an important therapeutic tool for treating neurological diseases. Mesenchymal stem cells (MSCs), as pluripotent stem cells, have great therapeutic potential for neurological diseases due to their regenerative ability, immunity, and ability to regulate inflammation. However, recent studies have shown that MSC-derived exosomes (MSC-Exos) play a major role in this process and play a key role in neuroprotection by regulating neuroglia. This review summarizes the recent progress made in regulating neuroinflammation by focusing on the mechanisms by which MSC-Exos are involved in the regulation of glial cells through signaling pathways such as the TLR, NF-κB, MAPK, STAT, and NLRP3 pathways to provide some references for subsequent research and therapy.
Graphical Abstract
Exosomes derived from MSCs exhibit neuroprotective effects by regulating signaling pathways and mitigating neuroinflammation triggered by glial cells.
The high prevalence of neurodegenerative diseases is an unintended consequence of the high longevity of the population, together with the lack of effective preventive and therapeutic options. There is great pressure on preclinical research, and both old and new models of neurodegenerative diseases are required to increase the pipeline of new drugs for clinical testing. We review here the main models of neurotoxicity-based animal models leading to central neurodegeneration. Our main focus was on studying how changes in neurotransmission and neuroinflammation, mainly in rodent models, contribute to harmful processes linked to neurodegeneration. The majority of the models currently in use mimic Parkinson’s disease (PD) and Alzheimer’s disease (AD), which are the most common neurodegenerative conditions in older adults. AD is the most common age-related dementia, whereas PD is the most common movement disorder with also cases of dementia. Several natural toxins and xenobiotic agents induce dopaminergic neurodegeneration and can reproduce neuropathological traits of PD. The literature analysis of MPTP, 6-OH-dopamine, and rotenone models suggested the latter as a useful model when specific doses of rotenone were administrated systemically to C57BL/6 mice. Cholinergic neurodegeneration is mainly modelled with the toxin scopolamine, which is a useful rodent model for the screening of protective drugs against cognitive decline and AD. Several agents have been used to model neuroinflammation-based neurodegeneration and dementia in AD, including lipopolysaccharide (LPS), streptozotocin, and monomeric C-reactive protein. The bacterial agent LPS makes a useful rodent model for testing anti-inflammatory therapies to halt the development and severity of AD. However, neurotoxin models might be more useful than genetic models for drug discovery in PD but that is not the case in AD where they cannot beat the new developments in transgenic mouse models. Overall, we should work using all available models, either in vivo, in vitro, or in silico, considering the seriousness of the moment and urgency of developing effective drugs.
