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Inflammation Jun 2024This study investigates the role of autophagy regulation in modulating neuroinflammation and cognitive function in an Alzheimer's disease (AD) mouse model with chronic...
This study investigates the role of autophagy regulation in modulating neuroinflammation and cognitive function in an Alzheimer's disease (AD) mouse model with chronic cerebral hypoperfusion (CCH). Using the APP23/PS1 mice plus CCH model, we examined the impact of autophagy regulation on cognitive function, neuroinflammation, and autophagic activity. Our results demonstrate significant cognitive impairments in AD mice, exacerbated by CCH, but mitigated by treatment with the autophagy inhibitor 3-methyladenine (3-MA). Dysregulation of autophagy-related proteins, accentuated by CCH, underscores the intricate relationship between cerebral blood flow and autophagy dysfunction in AD pathology. While 3-MA restored autophagic balance, rapamycin (RAPA) treatment did not induce significant changes, suggesting alternative therapeutic approaches are necessary. Dysregulated microglial polarization and neuroinflammation in AD+CCH were linked to cognitive decline, with 3-MA attenuating neuroinflammation. Furthermore, alterations in M2 microglial polarization and the levels of inflammatory markers NLRP3 and MCP1 were observed, with 3-MA treatment exhibiting potential anti-inflammatory effects. Our findings shed light on the crosstalk between autophagy and neuroinflammation in AD+CCH and suggest targeting autophagy as a promising strategy for mitigating neuroinflammation and cognitive decline in AD+CCH.
PubMed: 38951357
DOI: 10.1007/s10753-024-02043-0 -
Journal of Human Genetics Jul 2024Observational studies suggested increased risks of Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in patients with Crohn's disease (CD)...
Observational studies suggested increased risks of Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to assess the causality for the associations of CD and UC with the risks of AD, PD, and MS through a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms associated with CD (17,897 cases and 33,977 controls) and UC (13,768 cases and 33,977 controls) were identified as genetic instruments based on a European-descent genome-wide association study (GWAS) released by the International Inflammatory Bowel Disease Genetics Consortium. Summary statistics for AD (combined: 25,881 cases and 256,837 controls), PD (combined: 35,836 cases and 665,686 controls), and MS (combined: 48,477 cases and 285,515 controls) were obtained from the largest GWASs and FinnGen study of European ancestry, respectively. MR estimates were generated using the inverse-variance weighted method in the main analysis with a series of sensitivity analyses. MR analyses were conducted per outcome database and were subsequently meta-analyzed to generate combined estimates. Genetically predicted UC was significantly associated with increased risks of AD (combined: OR, 1.03; 95% CI, 1.01-1.05; P = 1.80 × 10) and MS (combined: OR, 1.37; 95% CI, 1.23-1.53; P = 1.18 × 10), while there was no association between genetically predicted UC and the risk of PD. In contrast, no significant associations were observed for genetically predicted CD with AD, PD, and MS. MR-Egger regression showed no directional pleiotropy for the identified associations, and sensitivity analyses with different MR methods further confirmed these findings. This study suggested significant adverse effects of UC on AD and MS, highlighting that UC patients should receive early intervention with optimal adjunctive medical therapy to reduce the risks of AD and MS.
PubMed: 38951193
DOI: 10.1038/s10038-024-01271-4 -
Experimental & Molecular Medicine Jul 2024The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying...
The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying mechanisms through which Aβ contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aβ induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aβ accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aβ-induced tau uptake in AD.
PubMed: 38951140
DOI: 10.1038/s12276-024-01274-3 -
ENeuro Jul 2024
Topics: Alzheimer Disease; Humans; Antibodies, Monoclonal, Humanized
PubMed: 38951040
DOI: 10.1523/ENEURO.0319-23.2024 -
Ageing Research Reviews Jun 2024Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aβ deposition that leads to the... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aβ deposition that leads to the degeneration or death of neurons. In addition to that, glucose-6-phosphate dehydrogenase (G6PD) has a multifaceted role in the process of AD development, where it can be used as both a marker and a target. G6PD activity is dysregulated due to its contribution to oxidative stress, neuroinflammation, and neuronal death. In this context, the current review presents a vivid depiction of recent findings on the relationship between AD progression and changes in the expression or activity of G6PD. The efficacy of the proposed G6PD-based therapeutics has been demonstrated in multiple studies using AD mouse models as representative animal model systems for cognitive decline and neurodegeneration associated with this disease. Innovative therapeutic insights are made for the boosting of G6PD activity via novel innovative nanotechnology and microfluidics tools in drug administration technology. Such approaches provide innovative methods of surpassing the blood-brain barrier, targeting step-by-step specific neural pathways, and overcoming biochemical disturbances that accompany AD. Using different nanoparticles loaded with G6DP to target specific organs, e.g., G6DP-loaded liposomes, enhances BBB penetration and brain distribution of G6DP. Many nanoparticles, which are used for different purposes, are briefly discussed in the paper. Such methods to mimic BBB on organs on-chip offer precise disease modeling and drug testing using microfluidic chips, requiring lower sample amounts and producing faster findings compared to conventional techniques. There are other contributions to microfluid in AD that are discussed briefly. However, there are some limitations accompanying microfluidics that need to be worked on to be used for AD. This study aims to bridge the gap in understanding AD with the synergistic use of promising technologies; microfluid and nanotechnology for future advancements.
PubMed: 38950868
DOI: 10.1016/j.arr.2024.102394 -
Ageing Research Reviews Jun 2024The blood brain barrier (BBB) is an indispensable structure that maintains the central nervous system (CNS) microenvironment for a correct neuronal function. It is... (Review)
Review
The blood brain barrier (BBB) is an indispensable structure that maintains the central nervous system (CNS) microenvironment for a correct neuronal function. It is composed by high specialized microvessels, surrounded by astrocytes, pericytes, neurons and microglia cells, which tightly control the influx and efflux of substances to the brain parenchyma. During aging, the BBB becomes impaired, and it may contribute to the development of neurodegenerative and neurological disorders including Alzheimer's disease and other dementias. Restoring BBB can be a strategy to prevent disease onset and development, reducing the symptoms of these conditions. This work critically reviews the major mechanisms underlying BBB breakdown in healthy and unhealthy aging, as well as biomarkers and methodologies that accurately assess its impairment. Complementarily, potential therapeutic targets are discussed as new strategies to restore the normal function of the BBB in aging.
PubMed: 38950867
DOI: 10.1016/j.arr.2024.102395 -
Mechanisms of Ageing and Development Jun 2024Oligodendrocyte precursor cells (OPCs) comprise 5-8% of the adult glial cell population and stand out as the most proliferative cell type in the central nervous system...
Oligodendrocyte precursor cells (OPCs) comprise 5-8% of the adult glial cell population and stand out as the most proliferative cell type in the central nervous system (CNS). OPCs are responsible for generating oligodendrocytes (OLs), the myelinating cells of the CNS. However, OPC functions decline as we age, resulting in impaired differentiation and inadequate remyelination. This review explores the cellular and molecular changes associated with OPC aging, and their impact on OPC differentiation and functionality. Furthermore, it examines the impact of OPC aging within the context of multiple sclerosis and Alzheimer's disease, both neurodegenerative conditions wherein aged OPCs exacerbate disease progression by impeding remyelination. Moreover, various pharmacological interventions targeting pathways related to senescence and differentiation are discussed as potential strategies to rejuvenate aged OPCs. Enhancing our understanding of OPC aging mechanisms holds promise for developing new therapies to improve remyelination and repair in age-related neurodegenerative disorders.
PubMed: 38950628
DOI: 10.1016/j.mad.2024.111959 -
Neurochemistry International Jun 2024Alumunium usage and toxicity has been a global concern especially an increased use of nanoparticulated aluminum (Al-NPs) products from the environment and the workplace....
Naringenin Mitigates Nanoparticulate-Aluminium Induced Neuronal Degeneration in Brain Cortex and Hippocampus through Downregulation of Oxidative Stress and Neuroinflammation.
Alumunium usage and toxicity has been a global concern especially an increased use of nanoparticulated aluminum (Al-NPs) products from the environment and the workplace. Al degrades in to nanoparticulate form in the environment due to the routine process of bioremediation in human body. Al-NPs toxicity plays key role in the pathophysiology of neurodegeneration which is characterised by the development of neurofibrillary tangles and neuritic plaques which correlates to the Alzheimer's disease. This study evaluated the Al-NPs induced neurodegeneration and causative behavioral alterations due to oxidative stress, inflammation, DNA damage, β-amyloid aggregation, and histopathological changes in mice. Furthermore, the preventive effect of naringenin (NAR) as a potent neuroprotective flavonoid against Al-NPs induced neurodegeneration was assessed. Al-NPs were synthesized and examined using FTIR, XRD, TEM, and particle size analyzer. Mice were orally administered with Al-NPs (6 mg/kg b.w.) followed by NAR treatment (10 mg/kg b.w. per day) for 66 days. The spatial working memory was determined by novel object recognition, T-maze, Y-maze, and Morris Water Maze tests. We measured nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidised glutathione, and acetylcholine esterase, as well as cytokines analysis, immunohistochemistry, and DNA damage. Al-NPs significantly reduced the learning memory power, increased oxidative stress, reduced antioxidant enzymatic activity, increased DNA damage, altered the levels of cytokines, and increased β-amyloid aggregation in the cortex and hippocampus regions of the mice brain. These neurobehavioral impairments, neuronal oxidative stress, and histopathological alterations were significantly attenuated by NAR supplementation. In conclusion, Al-NPs may be potent neurotoxic upon exposure and that NAR could serve as a potential preventive measure in the treatment and management of neuronal degeneration.
PubMed: 38950625
DOI: 10.1016/j.neuint.2024.105799 -
Talanta Jun 2024Alzheimer's disease (AD) has gradually received enthusiastic attention with the aging process, and studying its biological relevance is expected. Excitingly,...
Alzheimer's disease (AD) has gradually received enthusiastic attention with the aging process, and studying its biological relevance is expected. Excitingly, fluorescence probes were considered to be powerful tools for exploring biological correlations. Therefore, a highly selective near-infrared (NIR) fluorescent probe (DCM-Cl-Acr) for imaging cysteine (Cys) in AD was designed and synthesized. Through structural optimization, the probe exhibited high fluorescence quantum yield and low detection limit (20 nM) towards Cys. Meanwhile, based on the high selectivity and high sensitivity response exhibited by the probe to Cys, it was successfully applied to visualize endogenous and exogenous Cys in living cells and zebrafish, and showed good discrimination from homocysteine (Hcy) and glutathione (GSH). Further, the correlation between AD and Cys concentration was clarified by imaging studies in hippocampus tissue of AD mouse, and the abnormal accumulation of Cys in the hippocampus of AD brain was demonstrated.
PubMed: 38950502
DOI: 10.1016/j.talanta.2024.126482 -
Biochemical and Biophysical Research... Jun 2024In human Alzheimer's disease (AD), the aggregation of tau protein is considered a significant hallmark, along with amyloid-beta. The formation of neurofibrillary tangles...
In human Alzheimer's disease (AD), the aggregation of tau protein is considered a significant hallmark, along with amyloid-beta. The formation of neurofibrillary tangles due to aberrant phosphorylation of tau disrupts microtubule stability, leading to neuronal toxicity, dysfunction, and subsequent cell death. Nesfatin-1 is a neuropeptide primarily known for regulating appetite and energy homeostasis. However, the function of Nesfatin-1 in a neuroprotective role has not been investigated. In this study, we aimed to elucidate the effect of Nesfatin-1 on tau pathology using the Drosophila model system. Our findings demonstrate that Nesfatin-1 effectively mitigates the pathological phenotypes observed in Drosophila human Tau overexpression models. Nesfatin-1 overexpression rescued the neurodegenerative phenotypes in the adult fly's eye and bristle. Additionally, Nesfatin-1 improved locomotive behavior, neuromuscular junction formation, and lifespan in the hTau AD model. Moreover, Nesfatin-1 controls tauopathy by reducing the protein level of hTau. Overall, this research highlights the potential therapeutic applications of Nesfatin-1 in ameliorating the pathological features associated with Alzheimer's disease.
PubMed: 38950494
DOI: 10.1016/j.bbrc.2024.150311