Amyloid-β Aggregation Research Articles

MK886 Ameliorates Alzheimer's Disease by Activating the PRKCI/AKT Signaling Pathway.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, associated with oxidative stress, neuronal apoptosis, and the accumulation of amyloid-β (Aβ) plaques. Despite advances in understanding AD pathology, effective treatments remain limited. This study aimed to investigate the therapeutic efficacy and underlying molecular mechanisms of MK886, a selective inhibitor of the 5-lipoxygenase pathway, in the context of AD. Network pharmacology analyses were employed to evaluate MK886's potential as a treatment for AD, revealing promising interactions with key molecular targets implicated in the disease. In vitro experiments demonstrated that MK886 effectively mitigated Aβ1-42 oligomer-induced oxidative stress, apoptosis, and ferroptosis in mouse hippocampal neuronal cells (HT22). These effects were validated using techniques such as immunofluorescence, JC-1 staining, TUNEL staining, and flow cytometry. In vivo studies involved administering MK886 to APPswe/PS1dE9 (APP/PS1) mice, which resulted in significant improvements in cognitive and emotional functions as assessed by the Y-maze and Morris water maze tests. Histological evaluations, including Nissl staining, immunofluorescence, and immunohistochemistry, revealed that MK886 preserved hippocampal neuron integrity and reduced Aβ deposition. Proteomics and molecular docking analyses identified the PRKCI/AKT signaling pathway as a key mediator of MK886's neuroprotective effects. This finding was further validated through Western blotting experiments incorporating an AKT inhibitor. Overall, these findings suggest that MK886 holds promise as a potential therapeutic agent for Alzheimer's disease by enhancing neuronal protection and cognitive function through the activation of the PRKCI/AKT pathway.

Triple-Target Inhibition of Cholinesterase, Amyloid Aggregation, and GSK3β to Ameliorate Cognitive Deficits and Neuropathology in the Triple-Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) poses one of the most urgent medical challenges in the 21st century as it affects millions of people. Unfortunately, the etiopathogenesis of AD is not yet fully understood and the current pharmacotherapy options are somewhat limited. Here, we report a novel inhibitor, Compound 44, for targeting cholinesterases, amyloid-β (Aβ) aggregation, and glycogen synthase kinase 3β (GSK-3β) simultaneously with the aim of achieving symptomatic relief and disease modification in AD therapy. We found that Compound 44 had good inhibitory effects on all intended targets with IC50s of submicromolar or better, significant neuroprotective effects in cell models, and beneficial improvement of cognitive deficits in the triple transgenic AD (3 × Tg AD) mouse model. Moreover, we showed that Compound 44 acts as an autophagy regulator by inducing nuclear translocation of transcription factor EB through GSK-3β inhibition, enhancing the biogenesis of lysosomes and elevating autophagic flux, thus ameliorating the amyloid burden and tauopathy, as well as mitigating the disease phenotype. Our results suggest that triple-target inhibition via Compound 44 could be a promising strategy that may lead to the development of effective therapeutic approaches for AD.

Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response.

This study investigates the potential of arimoclomol-loaded nanomicelles for the treatment of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as their anti-inflammatory properties. Arimoclomol, a coinducer of heat shock proteins (HSPs), has shown clinical promise in mitigating protein misfolding, a hallmark of these diseases. In this work, arimoclomol nanomicelles significantly reduced the aggregation of β-amyloid (Aβ1-42) and α-synuclein (α-syn), key pathological proteins in Alzheimer's and Parkinson's. Additionally, the nanomicelles demonstrated potent anti-inflammatory effects, reducing leukocyte and neutrophil counts in an acute inflammation model. These results suggest that arimoclomol nanomicelles could enhance clinical outcomes by targeting both neurodegenerative and inflammatory processes, offering a promising therapeutic strategy for long-term disease management.

Charge Modification of Lysine Mitigates Amyloid-β Aggregation.

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides, which aggregate into toxic structures such as oligomers, fibrils, and plaques. The presence of these Aβ aggregates in the brain plays a crucial role in the pathophysiology, leading to synaptic dysfunction and cognitive impairment. Understanding how physiological factors affect Aβ aggregation is essential, and therefore, exploring their influence in vitro will likely provide insights into their role in AD pathology. In this study, we investigated the effects of physiological, free amino acids on Aβ aggregation dynamics. We focused on positively charged amino acids, particularly lysine, and employed a chemical modification, methylation, to neutralize its charge. Our analyses revealed that modified lysine significantly reduced Aβ aggregation, indicating that charge distribution of amino acids plays a crucial role in modulating Aβ aggregation behavior. These findings enhance our understanding of the regulatory factors influencing Aβ aggregation and highlight important considerations for future research on Aβ.

How Can Early Stress Influence Later Alzheimer's Disease Risk? Possible Mediators and Underlying Mechanisms.

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder to which genetic mutations and risk factors contribute. Evidence is increasing that environmental and lifestyle-related factors, such as exercise, nutrition, education, and exposure to (early-life) stress modify the onset, incidence, and progression of AD. Here, we discuss recent preclinical findings on putative substrates that can explain or contribute to the effects of stress early in life on the risk of developing AD. We focus in particular on stress hormones, neural networks, synapses, mitochondria, nutrient and lipid metabolism, adult neurogenesis, engram cell ensembles, and neuroinflammation. We discuss the idea that stress exposure early in life can alter these processes, either combined or in isolation, thereby reducing the capacity of the brain to resist deleterious consequences of, for example, amyloid-β accumulation, thereby accelerating cognitive decline and progression of Alzheimer-related changes in model systems of the disease. A better understanding of whether experiences early in life also modify trajectories of cognitive decline and pathology in AD and how the substrates discussed translate to humans may help develop novel preventive and/or therapeutic strategies to mitigate the consequences of stressors early in life and increase resilience to developing dementia.

Biofilm-modified Prussian blue improves memory function in late-stage Alzheimer's disease mice with triple therapy.

Alzheimer's disease (AD) is a neurodegenerative disease that is significantly characterized by cognitive and memory impairments, which worsen significantly with age. In the late stages of AD, metal ion disorders and an imbalance of reactive oxygen species (ROS) levels occur in the brain microenvironment, which causes abnormal aggregation of β-amyloid (Aβ), leading to a significant worsening of the AD symptoms. Therefore, we designed a composite nanomaterial of macrophage membranes-encapsulated Prussian blue nanoparticles (PB NPs/MM). Prussian blue nanoparticles (PB NPs) are capable of chelating Cu2+ and reducing ROS. Macrophage membranes (MM) have advantages over liposomal and erythrocyte membrane carriers, including inflammatory targeting capabilities and more effective immune evasion. Concurrently, the excellent photothermal ability of PB NPs can briefly open the blood-brain barrier (BBB) under near-infrared laser irradiation, which improves the transport efficiency of PB NPs/MM across the BBB and ablates Aβ deposition, thus achieving optimal therapeutic efficacy. In vitro experiments demonstrated that PB NPs/MM is a multifunctional nanosystem, which can effectively inhibit Cu2+-induced Aβ monomers aggregation, photothermally depolymerize Aβ fibrils, and attenuate oxidative stress through the combined treatment of chelating metals, photothermal therapy and scavenging ROS. In behavioral experiments, it also significantly improved the cognitive and learning deficits in late-stage APP/PS1 mice, thereby providing new ideas for the treatment of late-stage AD and other neurodegenerative diseases.

Quantification of amyloid-β aggregation inhibitors gallic acid and rosmarinic acid in biological samples by LC-MS/MS.

The decline of the cognitive functions encountered at patients diagnosed with Alzheimer's disease (AD) together with the findings of extracellular amyloid deposits, intracellular neurofibrillary tangles and microvascular angiopathy in brain were described at beginning of the 20th century. According to the amyloid cascade hypothesis, the overproduction of amyloid-β peptide and its aggregation into neurotoxic oligomers, fibrils, and amyloid plaques is considered the cause of AD. Amyloid-β fibril formation was experimentally proven in vitro using thioflavin T assay in the absence of interfering chemical compounds and the assay became an analytical tool for assessing the effects of different molecules against amyloid-β aggregation. Recent research studies provided experimental results that indicated the reduction of fibril formation by gallic acid and rosmarinic acid. Mass spectrometry was often employed in studies aiming at identifying, characterizing, and quantitating chemical compounds able to modify the progress of AD. The purpose of this review is to present current research studies regarding the identification and quantitation of the water-soluble gallic acid and rosmarinic acid in biological samples using liquid chromatographs coupled to triple quadrupole mass spectrometers as bioanalytical tools. The present study highlights the presence and amount of these chemical compounds in commonly used medicinal plants and culinary herbs and provides a list of extraction and liquid chromatography coupled to electrospray-triple quadrupole mass spectrometry methods examples described in previous pharmacokinetic studies. The article underlines the bioavailability and safety of gallic acid and rosmarinic acid for further research studies aiming at preventing and slowing the progress of AD.

Xinnaoxin capsule alleviates neuropathological changes and cognitive deficits in Alzheimer's disease mouse model induced by D-galactose and aluminum chloride via reducing neuroinflammation and protecting synaptic proteins.

Originally formulated to mitigate high-altitude sickness, Xinnaoxin capsules (XNX) are composed of three traditional Chinese medicines (Rhodiola rosea L., Lycium barbarum L. and Hippophae rhamnoides) with properties of anti-hypoxia, anti-fatigue, and anti-aging. Emerging evidence now suggests that XNX may also offer therapeutic benefits in Alzheimer's disease (AD), highlighting its potential significance in the development of novel AD treatments. This study aims to investigate whether XNX improves AD-related behavioral and cognitive deficits by enhancing antioxidant defenses, reducing peripheral and neuroinflammation, and protecting neurons. The AD mouse model was established using D-galactose and aluminum chloride. Spatial memory and anxiety-like behaviors were assessed via the Morris water maze and open field tests to evaluate the therapeutic effects of XNX. Biochemical markers in hippocampal tissue and serum were measured using ELISA kits, while serum chemical composition was analyzed by LC-MS. Histopathological changes and amyloid-β deposition in the hippocampus were examined through hematoxylin-eosin (HE) staining and immunofluorescence. Additionally, hippocampal expression of apoptotic proteins Bax and Caspase-3, anti-apoptotic protein Bcl-2, and synaptic proteins PSD-95 and Syn were assessed via Western blot. Behavioral tests demonstrated that XNX significantly improved spatial learning and memory abilities, as well as reduced anxiety-like behaviors in AD mice. XNX also modulated inflammatory cytokines and oxidative stress markers in hippocampal tissue and serum, while reducing amyloid-β deposition. Further LC-MS analysis of serum revealed a marked upregulation of compounds such as adenosine following treatment, with key metabolic pathways affected, including linoleic acid metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis. HE staining and immunofluorescence indicated that XNX ameliorated neuronal damage and decreased amyloid-β accumulation. Western blot analysis confirmed that XNX inhibited neuronal apoptosis and preserved synaptic proteins in the hippocampus. XNX mitigates AD-induced behavioral and cognitive deficits by enhancing antioxidant defenses, reducing peripheral and neuroinflammation, and protecting neurons. Our findings provide valuable data and a theoretical foundation for the potential therapeutic application of XNX in AD treatment and its further development.

The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal loss and cognitive impairment (CI). The: Cysteine-X-cysteine chemokine ligand 12(CXCL12)/CXC chemokine receptor type 4 (CXCR4)/CXC chemokine receptor type 7 (CXCR7) axis has emerged as a critical molecular pathway in the development of CI in these disorders. This review explores the role of this axis in the pathogenesis of CI across these neurodegenerative diseases, synthesizing current evidence and its implications for targeted therapies. In AD, dysregulation of this axis contributes to amyloid-β accumulation and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. PD studies reveal that CXCL12/CXCR4 signaling influences dopaminergic neuron survival and microglial activation, affecting cognitive function. In MS, the axis modulates neuroinflammation and demyelination processes, impacting cognitive performance. ALS research indicates that the CXCL12/CXCR4/CXCR7 pathway is involved in motor neuron degeneration and associated cognitive deficits. Across these diseases, the axis influences neuroinflammation, synaptic plasticity, and neuronal survival through various signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways. Emerging evidence suggests that modulating this axis could provide neuroprotective effects and potentially alleviate cognitive symptoms. This review highlights the potential of the CXCL12/CXCR4/CXCR7 axis as a therapeutic target for addressing CI in neurodegenerative diseases. It also underscores the need for further research to fully elucidate its role and develop effective interventions, potentially leading to improved clinical management strategies for these devastating disorders.

Non-coding RNAs in the pathogenesis of Alzheimer's disease: β-amyloid aggregation, Tau phosphorylation and neuroinflammation.

Alzheimer's disease is a progressive neurodegenerative disorder primarily affecting individuals aged 65 and older, characterized by cognitive decline and diminished quality of life. The molecular hallmarks of AD include extracellular β-amyloid plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, and chronic neuroinflammation. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as potential therapeutic targets due to their regulatory roles in AD pathogenesis. For example, miR-124 has been shown to modulate Aβ levels, while lncRNAs such as BACE1-AS regulate the expression of BACE1, a crucial enzyme in Aβ production. Transcriptomic studies of AD patients have revealed dysregulation of ncRNA expression, further supporting their involvement in disease progression. This review examines the regulatory functions of ncRNAs in AD, focusing on their impact on Aβ, tau hyperphosphorylation, and neuroinflammation. Additionally, we discuss the emerging role of ncRNAs in liquid-liquid phase separation and the formation of protein aggregates, key processes contributing to AD pathology.

Protective Effects of Bifidobacterium Breve MCC1274 as a Novel Therapy for Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by memory impairment that significantly interferes with daily life. Therapeutic options for AD that substantively modify disease progression remain a critical unmet need. In this regard, the gut microbiota is crucial in maintaining human health by regulating metabolism and immune responses, and increasing evidence suggests that probiotics, particularly beneficial bacteria, can enhance memory and cognitive functions. Recent studies have highlighted the positive effects of Bifidobacterium breve MCC1274 (B. breve MCC1274) on individuals with mild cognitive impairment (MCI) and schizophrenia. Additionally, oral supplementation with B. breve MCC1274 has been shown to effectively prevent memory decline in AppNL–G–F mice. In relation to Alzheimer’s pathology, oral supplementation with B. breve MCC1274 has been found to reduce amyloid-β (Aβ) accumulation and tau phosphorylation in both AppNL–G–F and wild-type (WT) mice. It also decreases microglial activation and increases levels of synaptic proteins. In this review, we examine the beneficial effects of B. breve MCC1274 on AD, exploring potential mechanisms of action and how this probiotic strain may aid in preventing or treating the disease. Furthermore, we discuss the broader implications of B. breve MCC1274 for improving overall host health and provide insights into future research directions for this promising probiotic therapy.

Distinct Aggregation Behavior of N-Terminally Truncated Aβ4-42 Over Aβ1-42 in the Presence of Zn(II).

The deposition of amyloid-β (Aβ) aggregates and metal ions within senile plaques is a hallmark of Alzheimer's disease (AD). Among the modifications observed in Aβ peptides, N-terminal truncation at Phe4, yielding Aβ4-x, is highly prevalent in AD-affected brains and significantly alters Aβ's metal-binding and aggregation profiles. Despite the abundance of Zn(II) in senile plaques, its impact on the aggregation and toxicity of Aβ4-x remains unexplored. Here, we report the distinct aggregation behavior of N-terminally truncated Aβ, specifically Aβ4-42, in the absence and presence of either Zn(II), Aβ seeds, or both, and compare it to that of full-length Aβ1-42. Our findings reveal notable differences in the aggregation profiles of Aβ4-42 and Aβ1-42, largely influenced by their different Zn(II)-binding properties. These results provide insights into the mechanisms underlying the distinct aggregation behavior of truncated and full-length Aβ in the presence of Zn(II), contributing to a deeper understanding of AD pathology.

Melatonin Overexpression in the Management of Alzheimer's Disease: Therapeutic Exploration.

Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by the accumulation of neurofibrillary tangles and β-amyloid plaques, leading to a decline in cognitive function. AD is characterized by tau protein hyperphosphorylation and extracellular β-amyloid accumulation. Even after much research, there are still no proven cures for AD. The neuroprotective, anti-inflammatory, and antioxidant qualities of melatonin, a hormone mostly produced by the pineal gland, have drawn interest as a possible treatment option for AD. This study looks at new evidence that suggests melatonin overexpression to be a promising therapy option for AD. Melatonin levels naturally decline with age and decrease more significantly in individuals with AD, worsening neurodegenerative processes. Melatonin has therapeutic potential as it inhibits Aβ formation, prevents amyloid fibril extension through structure-dependent interactions, and protects neurons from Aβ-induced toxicity. Melatonin promotes neurogenesis, which is decreased in AD, suggesting it may treat the disease's many pathologies. The review emphasizes the importance of melatonin's mechanisms of action, including its capacity to reduce neuroinflammation, regulate mitochondrial function, scavenge free radicals, and influence apoptotic pathways. As research into AD continues, this article provides a forward-looking perspective on how future studies could leverage melatonin's multifaceted neuroprotective properties to develop more effective treatments for AD.

Research Progress in the Molecular Mechanism of NLRP3 Inflammasome in Alzheimer's Disease and Regulation by Natural Plant Products.

Alzheimer's disease (AD) is a prominent neurodegenerative disorder affecting the central nervous system in the elderly. Current understanding of AD primarily centers on the gradual decline in cognitive and memory functions, believed to be influenced by factors including mitochondrial dysfunction, β-amyloid aggregation, and neuroinflammation. Emerging research indicates that neuroinflammation plays a significant role in the development of AD, with the inflammasome potentially mediating inflammatory responses that contribute to neurodegeneration. Recent studies in AD pathology have identified a novel form of inflammasome referred to as NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. Pathological alterations closely associated with NLRP3 inflammasome activation have been observed in the brain tissues of AD patients, transgenic mice, and in vitro neurocyte models. Numerous studies have demonstrated the potent neuroprotective properties of natural plant products (NPPs) against NLRP3 inflammasome-mediated AD pathology. This review provides a comprehensive examination of the NLRP3 inflammasome, its involvement in AD pathology, and the mechanisms underlying the therapeutic effects of NPP targeting the NLRP3 inflammasome.

Mapping of Amyloid-β Aggregates In Vivo by a Fluorescent Probe with Dual Recognition Moieties.

The spontaneous aggregation of amyloid-β (Aβ) leads to neuronal cell death in the brain and causes the development of Alzheimer's disease (AD). The efficient detection of the aggregation state of Aβ holds significant promise for the early diagnosis and subsequent treatment of this neurodegenerative disorder. Currently, most of the fluorescent probes used for the detection of Aβ fibrils share similar recognition moieties, such as the N,N-dimethylamino group, N,N-diethylamino group, and piperidyl group. The development of fluorescent probes incorporating novel recognition groups will, in principle, bring new properties for the detection and imaging of Aβ aggregates. Herein, we designed and synthesized three fluorescent probes (1 CarbCN, 2 NTCN, and 3 NCarbCN) based on dicyanoisophorone. The probe 3 NCarbCN, which integrated two recognition moieties, a carbamate unit (a new recognition group) together with a N,N-dimethylamino group, showed a sensitive turn-on fluorescence response toward the early aggregation state of Aβ, along with a high binding affinity (Kd = 59 nM) and recognition selectivity for Aβ fibrils. Theoretical calculations revealed that the carbamate unit of 3 NCarbCN could provide an additional three hydrogen bonding interaction with Aβ42 fibrils. Furthermore, the probe 3 NCarbCN efficiently crossed the blood-brain barrier and exhibited a higher response in the brains of AD model mice. Co-staining of isolated brain sections with monoclonal antibody further demonstrated specific binding of 3 NCarbCN to Aβ plaques in the brains of AD model mice, thus demonstrating its great potential for the early diagnosis of such neurodegenerative disorders.

Exploring Quinazoline as a Scaffold for Developing Novel Therapeutics in Alzheimer’s Disease

Quinazoline, a privileged scaffold in medicinal chemistry, offers promising potential in the synthesis of anti-Alzheimer’s disease (AD) drugs. This heterocyclic compound, characterized by its fused benzene and pyrimidine rings, enables the design of multifunctional agents targeting AD pathology. The drug-like aspects and pharmaceutical features of quinazoline derivatives have the potential to give rise to various therapeutic drugs. AD is a progressive neurodegenerative condition marked by memory decline, cognitive deterioration, and language disorders. Given its complexity and multifaceted nature, there is a pressing need to discover multi-target drugs to effectively address this debilitating disorder. A comprehensive literature review has demonstrated that quinazoline derivatives exhibit a wide range of therapeutic potential for AD. These compounds function as inhibitors of cholinesterases, β-amyloid aggregation, oxidative stress, and tau protein, among other protective effects. Here, we highlight the most significant and recent research on quinazoline-based anti-AD agents, aiming to support the development and discovery of novel treatments for AD.

Targeting SPI1 to mitigate amyloid-β pathology in Alzheimer's disease.

SPI1, a transcription factor implicated in myeloid cell development, has emerged as a genetic risk factor for Alzheimer's disease (AD). Recent in vivo studies reveal that Spi1 knockdown in mice exacerbates AD pathology by increasing amyloid-β aggregation and gliosis while Spi1 overexpression ameliorates these features. Transcriptomic analyses suggest that Spi1 regulates microglial immune response, complement activation, and phagocytosis. SPI1 regulation of these processes may explain how SPI1 affects AD risk. Further studies, including human validation, are needed to explore the dynamic influence of SPI1 across AD stages, its applicability to clinical settings, and its potential as a therapeutic target.

New Research on Biomarkers in Alzheimer's Continuum.

Alzheimer's disease (AD) is a multifactorial pathology, responsible for neurodegenerative disorders which in more than 60% of patients evolve into dementia. Comprehension of the molecular mechanisms underlying the pathology and the development of reliable diagnostic methods have made new and more effective therapies possible. In recent years, in addition to the classic anticholinesterases (AChEs), which can control the clinical symptoms of the disease, compounds able to reduce deposits of amyloid-β (Aβ) and/or tau (τ) protein aggregates, which are disease-modifying therapeutics (DMTs), have been studied. The results have shown that symptomatic therapy works best when administered in the disease's mild to moderate clinical phase. On the other hand, treatment with DMTs has been found to be more effective in the preclinical stage of AD, when Aβ and τ protein neurofibrillary tangles have not yet been compromised and patients still have a normal quality of life. This innovative approach requires the identification of specific biomarkers predictive of the disease, detectable many years before clinical signs are evident. Biomarkers allow early diagnosis, give indications of the possible development of dementia in the future, and make it possible to study the evolution of the disease. New scenarios, involving different pathways and approaches, could emerge and provide effective therapies to treat the very early stages of the disease and hamper its progression. The specific biomarkers studied so far have been reported here.

Harmony in Motion: The Role of Exercise in Orchestrating Neuroprotection for Individuals with Alzheimer's Disease and Diabetes Examined from a Psychological Perspective.

According to epidemiological studies, diabetes is more common in patients with AD, which suggests that diabetes is a significant risk factor for AD. Accelerating brain cell degeneration, worsening cognitive decline, and increasing susceptibility to AD can be attributed to pathogenic mechanisms linked to diabetes, such as impaired insulin signaling in the brain, neuroinflammation, oxidative stress, mitochondrial dysfunction, and vascular impairment. These factors can also lead to the accumulation of β-amyloid and tau protein phosphorylation. New research suggests that certain drugs used to manage diabetes have different levels of effectiveness in treating or preventing Alzheimer's disease. Exercise has numerous advantages, including the reduction of neuroinflammation, alleviation of oxidative stress and mitochondrial dysfunction, improvement of endothelial and cerebrovascular function, stimulation of neurogenesis, and prevention of pathological changes associated with diabetes-related Alzheimer's disease through various internal mechanisms. This study examined the development of Alzheimer's disease (AD) in relation to diabetes, evaluated the ability of specific antidiabetic drugs to prevent and treat AD, and investigated the impacts and underlying processes of exercise interventions in improving AD treatment for individuals with diabetes.

Lipid-induced condensate formation from the Alzheimer’s Aβ peptide triggers amyloid aggregation

The onset and development of Alzheimer's disease is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies at later stages of the disease, but the fundamental molecular steps in early stage disease that trigger the initial nucleation event leading to the conversion of monomeric Aβ peptide into pathological aggregates remain unknown. Here, we show that the Aβ peptide can form biomolecular condensates on lipid bilayers both in molecular assays and in living cells. Our results reveal that these Aβ condensates can significantly accelerate the primary nucleation step in the amyloid conversion cascade that leads to the formation of amyloid aggregates. We show that Aβ condensates contain phospholipids, are intrinsically heterogeneous, and are prone to undergo a liquid-to-solid transition leading to the formation of amyloid fibrils. These findings uncover the liquid-liquid phase separation behavior of the Aβ peptide and reveal a molecular step very early in the amyloid-β aggregation process.