Amyloid-β Aggregation Research Articles

Molecular docking and proteomics approaches for the identification of neuroprotective effects of IL15.5 peptide against oxidative stress-induced apoptosis in SH-SY5Y neurons

Amyloid-β (Aβ) aggregation is central to Alzheimer’s disease (AD), causing oxidative and synaptic damage. We developed IL15.5, a peptide-base inhibitor derived from IL15, a natural peptide from Siamese crocodile hemoglobin. Computational and molecular assays confirm IL15.5 effectively inhibits Aβ42 aggregation, evident in thioflavin T assay results. IL15.5 also demonstrates acetylcholinesterase inhibition and antioxidant activity. It protects SH-SY5Y cells from oxidative stress and apoptosis, influencing caspase 3/MAPK pathways. Proteomic analysis reveals the role of IL15.5 in oxidative stress mitigation, affecting proteins linked to DNA repair, inflammation, and cell migration, with a significant association with Ubiquitin C. These findings suggest the potential of IL15.5 as an anti-amyloidogenic agent for AD treatment, offering neuronal protection and highlighting its therapeutic promise.

Neurochemical organization of cortical proteinopathy and neurophysiology along the Alzheimer's disease continuum.

Despite parallel research indicating amyloid-β accumulation, alterations in cortical neurophysiological signaling, and multi-system neurotransmitter disruptions in Alzheimer's disease (AD), the relationships between these phenomena remains unclear. Using magnetoencephalography, positron emission tomography, and an atlas of 19 neurotransmitters, we studied the alignment between neurophysiological alterations, amyloid-β deposition, and the neurochemical gradients of the cortex. In patients with mild cognitive impairment and AD, changes in cortical rhythms were topographically aligned with cholinergic, serotonergic, and dopaminergic systems. These alignments correlated with the severity of clinical impairments. Additionally, cortical amyloid-β plaques were preferentially deposited along neurochemical boundaries, influencing how neurophysiological alterations align with muscarinic acetylcholine receptors. Most of the amyloid-β-neurochemical and alpha-band neuro-physio-chemical alignments replicated in an independent dataset of individuals with asymptomatic amyloid-β accumulation. Our findings demonstrate that AD pathology aligns topographically with the cortical distribution of chemical neuromodulator systems and scales with clinical severity, with implications for potential pharmacotherapeutic pathways. Changes in cortical rhythms in Alzheimer's are organized along neurochemical boundaries. The strength of these alignments is related to clinical symptom severity. Deposition of amyloid-β (Aβ) is aligned with similar neurotransmitter systems. Aβ deposition mediates the alignment of beta rhythms with cholinergic systems. Most alignments replicate in participants with pre-clinical Alzheimer's pathology.

Saponin components in Polygala tenuifolia as potential candidate drugs for treating dementia.

This study aims to elucidate the intervention effects of saponin components from Polygala tenuifolia Willd (Polygalaceae) on dementia, providing experimental evidence and new insights for the research and application of saponins in the field of dementia. This review is based on a search of the PubMed, NCBI, and Google Scholar databases from their inception to 13 May 2024, using terms such as "P. tenuifolia," "P. tenuifolia and saponins," "toxicity," "dementia," "Alzheimer's disease," "Parkinson's disease dementia," and "vascular dementia." The article summarizes the saponin components of P. tenuifolia, including tenuigenin, tenuifolin, polygalasaponins XXXII, and onjisaponin B, as well as the pathophysiological mechanisms of dementia. Importantly, it highlights the potential mechanisms by which the active components of P. tenuifolia prevent and treat diseases and relevant clinical studies. The saponin components of P. tenuifolia can reduce β-amyloid accumulation, exhibit antioxidant effects, regulate neurotransmitters, improve synaptic function, possess anti-inflammatory properties, inhibit neuronal apoptosis, and modulate autophagy. Therefore, P. tenuifolia may play a role in the prevention and treatment of dementia. The saponin components of P. tenuifolia have shown certain therapeutic effects on dementia. They can prevent and treat dementia through various mechanisms.

Ganoderic acid a decreased Aβ42-induced neurotoxicity in PC12 cells by reduced mitochondrial damage

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Accumulation of β-amyloid (Aβ) in the brain has been recognized as a key factor in the onset and progression of Alzheimer’s disease (AD).The accumulation of Aβ in the brain catalyzes the production of reactive oxygen species (ROS), which in turn triggers oxidative damage to cellular components such as DNA, lipids, and proteins. In the present study, we investigated the protective effect of Ganoderic acid A (GA.A) against Aβ42-induced apoptosis in PC12 cells. Changes in mitochondrial membrane potential indicated that GA.A treats mitochondrial dysfunction by decreasing Aβ42 deposition and inhibiting neural protofiber tangle formation. Changes in intracellular Ca2+ and caspase-3 indicated that GA.A reduced mitochondrial damage by Aβ42 in PC12 cells, thereby decreasing ROS accumulation and reducing Aβ protofiber-induced cytotoxicity. These features suggest that GA.A has great potential as an effective neuroprotective drug in the treatment of Alzheimer’s disease.

Rhei Undulati Rhizoma attenuates memory decline and reduces amyloid-β induced neuritic dystrophy in 5xFAD mouse

BackgroundAlzheimer's disease (AD) is a common type of dementia characterized by amyloid-β (Aβ) accumulation, lysosomal dysfunction, and tau hyperphosphorylation, leading to neurite dystrophy and memory loss. This study aimed to investigate whether Rhei Undulati Rhizoma (RUR), which has been reported to have anti-neuroinflammatory effect, attenuates Aβ-induced memory impairment, neuritic dystrophy, and tau hyperphosphorylation, and to reveal its mode of action.MethodsFive-month-old 5xFAD mice received RUR (50 mg/kg) orally for 2 months. The Y-maze test was used to assess working memory. After behavioral testing, brain tissue was analyzed using thioflavin S staining, western blotting, and immunofluorescence staining to investigate the mode of action of RUR. To confirm whether RUR directly reduces Aβ aggregation, a thioflavin T assay and dot blot were performed after incubating Aβ with RUR.ResultsRUR administration attenuated the Aβ-induced memory impairment in 5xFAD mice. Furthermore, decreased accumulation of Aβ was observed in the hippocampus of the RUR-treated 5xFAD group compare to the vehicle-treated 5xFAD group. Moreover, RUR reduced the dystrophic neurites (DNs) that accumulate impaired endolysosomal organelles around Aβ. In particular, RUR treatment downregulated the expression of β-site amyloid precursor protein cleaving enzyme 1 and the hyperphosphorylation of tau within DNs. Additionally, RUR directly suppressed the aggregation of Aβ, and eliminated Aβ oligomers in vitro.ConclusionsThis study showed that RUR could attenuate Aβ-induced pathology and directly regulate the aggregation of Aβ. These results suggest that RUR could be an efficient material for AD treatment through Aβ regulation.Graphical

Inhibition of the Early-Stage Cross-Amyloid Aggregation of Amyloid-β and IAPP via EGCG: Insights from Molecular Dynamics Simulations.

Amyloid-β (Aβ) and islet amyloid polypeptide (IAPP) are small peptides that have the potential to not only self-assemble but also cross-assemble and form cytotoxic amyloid aggregates. Recently, we experimentally investigated the nature of Aβ-IAPP coaggregation and its inhibition by small polyphenolic molecules. Notably, we found that epigallocatechin gallate (EGCG) had the ability to reduce heteroaggregate formation. However, the precise molecular mechanism behind the reduction of heteroaggregates remains unclear. In this study, the dimerization processes of Aβ40 and IAPP peptides with and without EGCG were characterized by the enhanced sampling technique. Our results showed that these amyloid peptides exhibited a tendency to form a stable heterodimer, which represented the first step toward coaggregation. Furthermore, we also found that the EGCG regulated the dimerization process. In the presence of EGCG, well-tempered metadynamics simulation indicated a notable shift in the bound state toward a greater center of mass (COM) distance. Additionally, the presence of EGCG led to a significant increase in the free energy barrier height (∼15k B T) along the COM distance, and we observed a transition state between the bound and unbound states. Our findings also unveiled that the EGCG formed a greater number of hydrogen bonds with Aβ40, effectively obstructing the dimer formation. In addition, we carried out microseconds of all-atom conventional molecular dynamics (cMD) simulations to investigate the formation of both hetero- and homo-oligomer states by these peptides. MD simulations illustrated that EGCG played a significant role in preventing oligomer formation by reducing the content of β-sheets in the peptide. Collectively, our results offered valuable insight into the mechanism of cross-amyloid aggregation between Aβ40 and IAPP and the inhibition effect of EGCG on the heteroaggregation process.

The Effect of Chronic Restraint Stress Induced Alzheimer Like Changes In Male Adult Rats

Abstract Chronic stress has become a common problem that cannot be ignored and has become an important risk factor for the onset of many diseases. Responses to chronic stress are systemic reactions involving multiple organs and can induce symptoms such as depression, cognitive impairment, cardiovascular disease, immune dysfunctions, impaired reproductive ability, bone loss, and reduced life expectancy. Aim The present study was designed to investigate the effect of chronic restraint stress on the cognitive function in male albino rats, further to demonstrate its relation to amyloid and tau protein accumulation. Methods 24-albino male wistar rats were divided into 2 groups as Control group and Chronic restraint stress (CRS) subjected group (done by restraining rats for 3 hours daily for 4 weeks). Body weight, morris water maze test (MWM) and brain levels of p tau and amyloid beta were investigated Results CRS increased body weight significantly in week 4 and increased latency time as observed in MWM test compared to control group. Additionally, p tau and amyloid beta levels in CRS group were significantly increased. Conclusion chronic stress is able to accelerate the appearance of Alzheimer’s disease (AD) Changes upon chronic stress in the brain were related to accumulation of β-amyloid, TAU hyperphosphorylation in males.

Comparison of deep learning architectures for predicting amyloid positivity in Alzheimer's disease, mild cognitive impairment, and healthy aging, from T1-weighted brain structural MRI.

Abnormal β-amyloid (Aβ) accumulation in the brain is an early indicator of Alzheimer's disease (AD) and is typically assessed through invasive procedures such as PET (positron emission tomography) or CSF (cerebrospinal fluid) assays. As new anti-Alzheimer's treatments can now successfully target amyloid pathology, there is a growing interest in predicting Aβ positivity (Aβ+) from less invasive, more widely available types of brain scans, such as T1-weighted (T1w) MRI. Here we compare multiple approaches to infer Aβ + from standard anatomical MRI: (1) classical machine learning algorithms, including logistic regression, XGBoost, and shallow artificial neural networks, (2) deep learning models based on 2D and 3D convolutional neural networks (CNNs), (3) a hybrid ANN-CNN, combining the strengths of shallow and deep neural networks, (4) transfer learning models based on CNNs, and (5) 3D Vision Transformers. All models were trained on paired MRI/PET data from 1,847 elderly participants (mean age: 75.1 yrs. ± 7.6SD; 863 females/984 males; 661 healthy controls, 889 with mild cognitive impairment (MCI), and 297 with Dementia), scanned as part of the Alzheimer's Disease Neuroimaging Initiative. We evaluated each model's balanced accuracy and F1 scores. While further tests on more diverse data are warranted, deep learning models trained on standard MRI showed promise for estimating Aβ + status, at least in people with MCI. This may offer a potential screening option before resorting to more invasive procedures.

The neuroinflammatory role of microglia in Alzheimer's disease and their associated therapeutic targets.

Alzheimer's disease (AD), the main cause of dementia, is characterized by synaptic loss and neurodegeneration. Amyloid-β (Aβ) accumulation, hyperphosphorylation of tau protein, and neurofibrillary tangles (NFTs) in the brain are considered to be the initiating factors of AD. However, this hypothesis falls short of explaining many aspects of AD pathogenesis. Recently, there has been mounting evidence that neuroinflammation plays a key role in the pathophysiology of AD and causes neurodegeneration by over-activating microglia and releasing inflammatory mediators. PubMed, Web of Science, EMBASE, and MEDLINE were used for searching and summarizing all the recent publications related to inflammation and its association with Alzheimer's disease. Our review shows how inflammatory dysregulation influences AD pathology as well as the roles of microglia in neuroinflammation, the possible microglia-associated therapeutic targets, top neuroinflammatory biomarkers, and anti-inflammatory drugs that combat inflammation. In conclusion, microglial inflammatory reactions are important factors in AD pathogenesis and need to be discussed in more detail for promising therapeutic strategies.

Amyloid-β but not tau accumulation is strongly associated with longitudinal cognitive decline.

Alzheimer's disease (AD) pathology is featured by the extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles in the brain. We studied whether Aβ and tau accumulation are independently associated with future cognitive decline in the AD continuum. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) public database. A total of 1272 participants were selected based on the availability of Aβ-PET and CSF tau at baseline and of those 777 participants with follow-up visits. We found that Aβ-PET and CSF tau pathology were related to cognitive decline across the AD clinical spectrum, both as potential predictors for dementia progression. Among them, Aβ-PET (A + T- subjects) is an independent reliable predictor of longitudinal cognitive decline in terms of ADAS-13, ADNI-MEM, and MMSE scores rather than tau pathology (A - T+ subjects), indicating tau accumulation is not closely correlated with future cognitive impairment without being driven by Aβ deposition. Of note, a high percentage of APOE ε4 carriers with Aβ pathology (A+) develop poor memory and learning capacity. Interestingly, this condition is not recurrence in terms of the ADNI-MEM domain when adding APOE ε4 status. Finally, the levels of Aβ-PET SUVR related to glucose hypometabolism more strongly in subjects with A + T- than A - T+ both happen at baseline and longitudinal changes. In conclusion, Aβ-PET alone without tau pathology (A + T-) measure is an independent reliable predictor of longitudinal cognitive decline but may nonetheless forecast different status of dementia progression. However, tau accumulation alone without Aβ pathology background (A - T+) was not enough to be an independent predictor of cognitive worsening.

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.

The Crosstalk Between Amyloid-β, Retina, and Sleep for the Early Diagnosis of Alzheimer's Disease: A Narrative Review.

Alzheimer's disease (AD) is the most common type of dementia, which is characterised by progressive memory loss and accumulation of hallmark markers amyloid-β (Aβ) and neurofibrillary tangles in the diseased brain. The current gold standard diagnostic methods have limitations of being invasive, costly, and not easily accessible. Thus, there is a need for new avenues, such as imaging the retina for early AD diagnosis. Sleep disruption is symptomatically frequent across preclinical and AD subjects. As circadian activity, such as the sleep-wake cycle, is linked to the retina, analysis of their association may be useful additions for achieving predictive AD diagnosis. In this narrative review, we provide an overview of human retina studies concerning the deposition of Aβ, the role of the retina in sleep-wake cycle, the disruption of sleep in AD, and to gather evidence for the associations between Aβ, the retina, and sleep. Understanding the mechanisms behind the associations between Aβ, retina, and sleep could assist in the interpretation of retinal changes accurately in AD.

Bifunctional halloysite nanotube-based Ripk1 siRNA delivery system rescues cognitive impairment by targeting amyloid β plaques for clearance and reducing necrotic neurons in Alzheimer’s disease mice

Alzheimer’s disease (AD) is exacerbated by abnormal accumulation of toxic β-amyloid (Aβ) aggregates and Aβ-mediated neuronal cell death. Currently, no effective drugs for AD treatment are mainly due to the blood–brain barrier hindrance, which limits the most drugs for application in AD treatment. Accumulating evidence suggests that increased levels of Ripk1 and enhancement of Ripk1-mediated neuronal necroptosis are known to play an important role in neuronal death in AD. Targeting Ripk1 by pharmacological or genetic inhibition of Ripk1 has been demonstrated to prevent neuronal necroptosis and improve memory deficits in AD mice models. Here, we showed that halloysite (HNTs), one of the nanoclays, absorbed Aβ and reduced toxic Aβ aggregate production by inhibiting fibril formation and promoting the clearance of Aβ plaques. We also presented evidence that RVG29, a brain-penetrating peptide, bound directly to Aβ species and inhibited Aβ aggregation. In addition, Ripk1 is more dramatically expressed around Aβ plaques than those far from plaques in the brain of AD mice. Therefore, we designed a novel Aβ plaque-targeted nanomedicine (SH-RVG/siRipk1) via functionalizing with RVG29 onto short HNTs (SH) and loading Ripk1 siRNA (siRipk1) into the lumen of SH to prevent siRipk1 degradation. As we expected, SH-RVG/siRipk1 not only reduced plaques and improved memory impairment but also rescued necrotic neuronal loss around plaques by reducing Ripk1 expression around plaques in AD mice. These findings indicate that SH-RVG/siRipk1 may be an effective strategy for the treatment of AD.

Olanzapine attenuates amyloid-β-induced microglia-mediated progressive neurite lesions

The accumulation of amyloid-β (Aβ) in the brain is the first pathological mechanism to initiate Alzheimer’s disease (AD) pathogenesis. However, the precise role of Aβ in the disease progression remains unclear. Through decades of research, prolonged inflammation has emerged as an important core pathology in AD. Previously, a study has demonstrated the neurotoxic effect of Aβ-induced neuroinflammation in neuron-glia co-culture at 72 h. Here, we hypothesise that initial stage Aβ may trigger microglial inflammation, synergistically contributing to the progression of neurite lesions relevant to AD progression. In the present study, we aimed to determine whether olanzapine, an antipsychotic drug possessing anti-inflammatory properties, can ameliorate Aβ-induced progressive neurite lesions. Our study reports that Aβ induces neurite lesions with or without inflammatory microglial cells in vitro. More intriguingly, the present study revealed that Aβ exacerbates neurite lesions in synergy with microglia. Moreover, the time course study revealed that Aβ promotes microglia-mediated neurite lesions by eliciting the secretion of pro-inflammatory cytokines. Furthermore, our study shows that olanzapine at lower doses prevents Aβ-induced microglia-mediated progressive neurite lesions. The increase in pro-inflammatory cytokines induced by Aβ is attenuated by olanzapine administration, associated with a reduction in microglial inflammation. Finally, this study reports that microglial senescence induced by Aβ was rescued by olanzapine. Thus, our study provides the first evidence that 1 µM to 5 µM of olanzapine can effectively prevent Aβ-induced microglia-mediated progressive neurite lesions by modulating microglial inflammation. These observations reinforce the potential of targeting microglial remodelling to slow disease progression in AD.

The impact of astrocytic NF-κB on healthy and Alzheimer’s disease brains

Astrocytes play a role in healthy cognitive function and Alzheimer’s disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)+-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.

Novel pyrrolidine-alkylamino-substituted dicyanoisophorone derivatives as near-infrared fluorescence probe for imaging β-amyloid in vitro and in vivo

BackgroundThe formation of amyloid-β (Aβ) plaques is one of the key neuropathological hallmarks of Alzheimer's disease (AD). Near-infrared (NIR) probes show great potential for imaging of Aβ plaques in vivo and in vitro. Dicyanoisophorone (DCIP) based Aβ probes have attracted considerable attention due to their exceptional properties. However, DCIP probes still has some drawbacks, such as short emission wavelength (<650 nm) and low fluorescence intensity after binding to Aβ. It is clear that further modification is needed to improve their luminescence efficiency and sensitivity. ResultsWe designed and synthesize four novel pyrrolidine-alkylamino-substituted DCIP derivatives (6a-d) as imaging agents for β-amyloid (Aβ) aggregates. Compound 6c responds better to Aβ aggregates than the other three compounds (6a, 6b and 6d) and its precursor DCIP. The calculated detection limit is to be as low as 0.23 μM. Compound 6c shows no cytotoxicity in the tested concentration for SH-SY5Y and HL-7702 cells. Additionally, compound 6c is successfully applied to monitor Aβ aggregates in live SH-SY5Y cells and APP/PS1 transgenic mice. The retention time in the transgenic mice brain is much longer than that of age-matched wild-type mice. SignificanceThe results indicates that compound 6c had an excellent ability to penetrate the blood-brain barrier and it could effectively distinguish APP/PS1 transgenic mice and wide-type mice. This represents its promising applications for Aβ detection in basic and biomedical research.

GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-β-Induced Alzheimer's Disease Animal Model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-β-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24h prior to intrahippocampal injection of amyloid-β. NFPS pretreatment prevented amyloid-β-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-β injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-β-induced hippocampal damage.

Optimization of quinolinium-carbazole theranostics for the improved photooxidation of β-amyloid aggregates with the variation of conjugation site

Alzheimer’s disease (AD), the most prevalent neurodegenerative condition, is characterized by a gradual decline in cognitive function and memory loss. Presently, it ranks as the fifth leading cause of death worldwide. Photodynamic therapy, with its operational flexibility, noninvasive approach, and high spatial and temporal resolution, has emerged as an innovative therapeutic method, enhancing therapeutic efficacy and minimizing systemic toxicity. In this work, we have designed two donor-π-acceptor (D-π-A) type photosensitizers targeting amyloid, differing in the donor and acceptor junction sites. Surprisingly we found that by altering the junction site of the donor and acceptor from the 2-position to the 3-position of carbazole, the binding affinity and singlet oxygen efficiency of compound 3-QM16 improved compared to compound 2-QM16. This modification facilitated β-amyloid imaging and photooxidative therapy. Our study might shed light on the further optimization of the photooxidation performance of photosensitizers on misfolded proteins.

Predicting conversion from mild cognitive impairment to Alzheimer's disease: a multimodal approach.

Successively predicting whether mild cognitive impairment patients will progress to Alzheimer's disease is of significant clinical relevance. This ability may provide information that can be leveraged by emerging intervention approaches and thus mitigate some of the negative effects of the disease. Neuroimaging biomarkers have gained some attention in recent years and may be useful in predicting the conversion of mild cognitive impairment to Alzheimer's disease. We implemented a novel multi-modal approach that allowed us to evaluate the potential of different imaging modalities, both alone and in different degrees of combinations, in predicting the conversion to Alzheimer's disease of mild cognitive impairment patients. We applied this approach to the imaging data from the Alzheimer's Disease Neuroimaging Initiative that is a multi-modal imaging dataset comprised of MRI, Fluorodeoxyglucose PET, Florbetapir PET and diffusion tensor imaging. We included a total of 480 mild cognitive impairment patients that were split into two groups: converted and stable. Imaging data were segmented into atlas-based regions of interest, from which relevant features were extracted for the different imaging modalities and used to construct machine-learning models to classify mild cognitive impairment patients into converted or stable, using each of the different imaging modalities independently. The models were then combined, using a simple weight fusion ensemble strategy, to evaluate the complementarity of different imaging modalities and their contribution to the prediction accuracy of the models. The single-modality findings revealed that the model, utilizing features extracted from Florbetapir PET, demonstrated the highest performance with a balanced accuracy of 83.51%. Concerning multi-modality models, not all combinations enhanced mild cognitive impairment conversion prediction. Notably, the combination of MRI with Fluorodeoxyglucose PET emerged as the most promising, exhibiting an overall improvement in predictive capabilities, achieving a balanced accuracy of 78.43%. This indicates synergy and complementarity between the two imaging modalities in predicting mild cognitive impairment conversion. These findings suggest that β-amyloid accumulation provides robust predictive capabilities, while the combination of multiple imaging modalities has the potential to surpass certain single-modality approaches. Exploring modality-specific biomarkers, we identified the brainstem as a sensitive biomarker for both MRI and Fluorodeoxyglucose PET modalities, implicating its involvement in early Alzheimer's pathology. Notably, the corpus callosum and adjacent cortical regions emerged as potential biomarkers, warranting further study into their role in the early stages of Alzheimer's disease.

Power of Dopamine: Multifunctional Compound Assisted Conversion of the Most Risk Factor into Therapeutics of Alzheimer's Disease.

In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-β (Aβ) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aβ-Cu2+ complex as Aβ peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu2+ ions from the Aβ-Cu2+ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu2+ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.