Search Results (686)

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

A series of rivastigmine hybrids, incorporating rivastigmine fragments (RIV) and a set of different antioxidant scaffolds, were designed, synthesized, and evaluated as multifunctional agents for the potential therapy of Alzheimer’s disease (AD). In vitro bioactivity assays indicated that some compounds have very good antioxidant (radical-scavenging) activity. The compounds also displayed good inhibitory activity against cholinesterases, though the bigger-sized hybrids showed higher inhibitory ability for butyrylcholinesterase (BChE) than for acetylcholinesterase (AChE), due to the larger active site cavity of BChE. All the hybrids exhibited an inhibition capacity for self-induced amyloid-β (Aβ_1–42) aggregation. Furthermore, cell assays demonstrated that some compounds showed capacity for rescuing neuroblastoma cells from toxicity induced by reactive oxygen species (ROS). Among these RIV hybrids, the best in vitro multifunctional capacity was found for the caffeic acid derivatives enclosing catechol moieties (4AY5, 4AY6), though the Trolox derivatives (4AY2, 4BY2) presented the best cell neuroprotective activity against oxidative damage. Molecular-docking studies provided structural insights into the binding modes of RIV-based hybrids to the cholinesterases, revealing key interaction patterns despite some lack of correlation with inhibitory potency. Overall, the balanced multifunctional profiles of these hybrids render them potentially promising candidates for treating AD, thus deserving further investigation. Full article

Amyloid-β (Aβ) aggregates are considered as the important factors of Alzheimer’s disease (AD). Multifunctional materials have shown significant effects in the diagnosis and treatment of AD by modulating the aggregation of Aβ and production of reactive oxygen species (ROS). Compared to traditional surgical treatment and radiotherapy, phototherapy has the advantages, including short response time, significant efficacy, and minimal side effects in disease diagnosis and treatment. Recent studies have shown that local thermal energy or singlet oxygen generated by irradiating certain organic molecules or nanomaterials with specific laser wavelengths can effectively degrade Aβ aggregates and depress the generation of ROS, promoting progress in AD diagnosis and therapy. Herein, we outline the development of photothermal therapy (PTT) and photodynamic therapy (PDT) strategies for the diagnosis and therapy of AD by modulating Aβ aggregation. The materials mainly include organic photothermal agents or photosensitizers, polymer materials, metal nanoparticles, quantum dots, carbon-based nanomaterials, etc. In addition, compared to traditional fluorescent dyes, aggregation-induced emission (AIE) molecules have the advantages of good stability, low background signals, and strong resistance to photobleaching for bioimaging. Some AIE-based materials exhibit excellent photothermal and photodynamic effects, showing broad application prospects in the diagnosis and therapy of AD. We further summarize the advances in the detection of Aβ aggregates and phototherapy of AD using AIE-based materials. Full article

Background/Objectives: Niemann-Pick disease Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 100,000 live births that belongs to the lysosomal storage diseases (LSDs). NPC is characterized by the abnormal accumulation of unesterified cholesterol, in addition to being an autosomal recessive inherited pathology, which belongs to LSDs. It occurs in 95% of cases due to mutations in the NPC1 gene, while 5% of cases are due to mutations in the NPC2 gene. In the cerebral cortex (CC), the disease shows lipid inclusions, increased cholesterol and multiple sphingolipids in neuronal membranes, and protein aggregates such as hyperphosphorylated tau, α-Synuclein, TDP-43, and β-amyloid peptide. Mitochondrial damage and oxidative stress are some alterations at the cellular level in NPC. Therefore, the aim of this work was to determine the gene expression profile in the CC of NPC1 mice in order to identify altered molecular pathways that may be related to the pathophysiology of the disease. Methods: In this study, we performed a microarray analysis of a 22,000-gene chip from the cerebral cortex of an NPC mutant mouse compared to a WT mouse. Subsequently, we performed a bioinformatic analysis in which we found groups of dysregulated genes, and their expression was corroborated by qPCR. Finally, we performed Western blotting to determine the expression of proteins probably dysregulated. Results: We found groups of dysregulated genes in the cerebral cortex of the NPC mouse involved in the ubiquitination, fatty acid metabolism, differentiation and development, and underexpression in genes with mitochondrial functions, which could be involved in intrinsic apoptosis reported in NPC, in addition, we found a generalized deregulation in the cortical circadian rhythm pathway, which could be related to the depressive behavior that has even been reported in NPC patients. Conclusions: Recognizing that there are changes in the expression of genes related to ubiquitination, mitochondrial functions, and cortical circadian rhythm in the NPC mutant mouse lays the basis for targeting treatments to new potential therapeutic targets. Full article

Candida fungal species are the most common fungal opportunistic pathogens. Their ability to form antifungal resistant biofilms contributes to their increasing clinical frequency. These fungi express surface-anchored adhesins including members of the Als family. These adhesins mediate epithelial adhesion, aggregation, and biofilm formation. Many of the adhesins contain cross-β core sequences that form amyloid-like protein aggregates on the fungal surface. The aggregates mediate high-avidity bonding that contributes to biofilm establishment and persistence. Accordingly, autopsy sections from individuals with candidiasis and other mycoses have amyloids within abscesses. An amyloid-forming peptide containing a sequence from Candida albicans Als5 bound to C. albicans, C. tropicalis, and C. parapsilosis. C. albicans and C. tropicalis aggregated with beads coated with serum albumin, and the aggregates stained with the amyloid-binding dye thioflavin T. Additionally, an Als5-derived amyloid-inhibiting peptide blocked cell aggregation. The amyloid-inhibiting peptide also blocked C. albicans, C. tropicalis, and C. parapsilosis adhesion to monolayers of FaDu epithelial cells. These results show the involvement of amyloid-like interactions in pathogenesis in several Candida species. Full article

Protein association and aggregation are fundamental processes that play critical roles in a variety of biological phenomena from cell signaling to the development of incurable diseases, including amyloidoses. Understanding the basic biophysical principles governing protein aggregation processes is of crucial importance for developing treatment strategies for diseases associated with protein aggregation, including sarcopenia, as well as for the treatment of pathological processes associated with the disruption of functional protein complexes. This work, using a set of methods such as atomic force microscopy (AFM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction, as well as bioinformatics analysis, investigated the structures of complexes formed by titin and myosin-binding protein C (MyBP-C). TEM revealed the formation of morphologically ordered aggregates in the form of beads during co-incubation of titin and MyBP-C under close-to-physiological conditions (175 mM KCl, pH 7.0). AFM showed the formation of a relatively homogeneous film with local areas of relief change. Fluorimetry with thioflavin T, as well as FTIR spectroscopy, revealed signs of an amyloid-like structure, including a signal in the cross-β region. X-ray diffraction showed the presence of a cross-β structure characteristic of amyloid aggregates. Such structural features were not observed in the control samples of the investigated proteins separately. In sarcomeres, these proteins are associated with each other, and this interaction plays a partial role in the formation of a strong sarcomeric cytoskeleton. We found that under physiological ionic-strength conditions titin and MyBP-C form complexes in which an amyloid-like structure is present. The possible functional significance of amyloid-like aggregation of these proteins in muscle cells in vivo is discussed. Full article

Amyloids are protein aggregates having a cross-β structure, and they reveal some unusual properties, like interactions with specific dyes and resistance to actions of detergents and proteases, as well as the capability to force some proteins to change their conformation from a soluble form to aggregates. The occurrence of amyloids is not restricted to humans and animals, as they also exist in microbial cells. However, contrary to animals, where amyloids are usually pathological molecules, bacterial amyloids are often functional, participating in various physiological processes. In this review, we focus on a specific property of bacterial amyloids, namely their ability to interact with nucleic acids and resultant regulatory mechanisms. Moreover, some of these interactions might play indirect roles in the pathomechanisms of human neurodegenerative and inflammatory diseases; these aspects are also summarized and discussed in this review. Full article

Peptide-induced disruption of lipid membranes is central to both amyloid diseases and the activity of antimicrobial peptides. Here, we combine all-atom molecular dynamics simulations with biophysical experiments to investigate how four amphipathic peptides interact with lipid bilayers. All peptides adsorb on the membrane surface. Peptide M01 [Ac-(FKFE)₂-NH₂] self-assembles into $\beta$-sheet nanofibrils that span both leaflets of the membrane, creating water-permeable channels. The other three peptides adopt $\alpha$-helical structures at the water–lipid interface. Peptide M02 [Ac-FFKKFFEE-NH₂], a sequence isomer of M01, does not form $\beta$-sheet aggregates and is too short to span the bilayer, resulting in no observable water permeation across the membrane. Peptides M03 and M04 are $\alpha$-helical isomers long enough to span the bilayer, with a polar face that allows the penetration of water deep inside the membrane. For the M03 peptide [Ac-(FFKKFFEE)₂-NH₂], insertion into the bilayer starts with the nonpolar N-terminal amino acids penetrating the hydrophobic core of the bilayer, while electrostatic interactions hold negative residues at the C-terminus on the membrane surface. The M04 peptide, [Ac-FFKKFFEEFKKFFEEF-NH₂], is made by relocating a single nonpolar residue from the central region of M03 to the C-terminus. This nonpolar residue becomes unfavorably exposed to the solvent upon insertion of the N-terminal region of the peptide into the membrane. Consequently, higher concentrations of M04 peptides are required to induce water permeation compared to M03. Overall, our comparative analysis reveals how subtle rearrangements of polar and nonpolar residues modulate peptide-induced water permeation. This provides mechanistic insights relevant to amyloid pathology and antimicrobial peptide design. Full article

Objectives: The compound 3-(4-Hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a terminal metabolite derived from polyphenol compounds. It has been studied for its potential to support brain health indirectly through its anti-oxidant effects and ability to enhance the gut environment; however, its role in dementia pathogenesis is unclear. Therefore, the aim of this study was to evaluate how HMPA inhibits Aβ42 aggregation in vitro. Methods: We examined the inhibitory effects of HMPA on amyloid-β protein (Aβ) aggregation using a thioflavin T (ThT) assay and electron microscopy (EM). Results: ThT assays demonstrated that HMPA inhibited both the nucleation and elongation phases of Aβ aggregation. Additionally, EM of low-molecular-weight (LMW) Aβ42 in the presence of HMPA demonstrated shorter fibrils compared to those formed without HMPA. The EC₅₀ of HMPA in LMW Aβ42 was 5–6 mM. Conclusions: These findings indicate that, similar to several polyphenol compounds such as myricetin and rosmarinic acid, HMPA may inhibit Aβ pathogenesis, although it requires a fairly high concentration in vitro. These findings suggest the potential of HMPA as a lead compound for modulating Aβ-related neurodegeneration. Full article

Familial Alzheimer’s disease (FAD) is caused by dominant missense mutations in amyloid precursor protein (APP) and presenilin-1 (PSEN1), the catalytic component of γ-secretase that generates amyloid β-peptides (Aβ) from the APP C-terminal fragment C99. While most FAD mutations increase the ratio of aggregation-prone Aβ42 relative to Aβ40, consistent with the amyloid hypothesis of Alzheimer pathogenesis, some mutations do not increase this ratio. The γ-secretase complex produces amyloid β-peptide (Aβ) through processive cleavage along two pathways: C99 → Aβ49 → Aβ46 → Aβ43 → Aβ40 and C99 → Aβ48 → Aβ45 → Aβ42 → Aβ38. Understanding how FAD mutations affect the multistep γ-secretase cleavage process is critical for elucidating disease pathogenesis. In a recent study, we discovered that FAD mutations lead to stalled γ-secretase/substrate complexes that trigger synaptic loss independently of Aβ production. Here, we further investigate this “stalled complex” hypothesis, focusing on five additional PSEN1 FAD mutations (M84V, C92S, Y115H, T116I, and M139V). A comprehensive biochemical analysis revealed that all five mutations led to substantially reduced initial proteolysis of C99 to Aβ49 or Aβ48 as well as deficiencies in one or more subsequent trimming steps. Results from fluorescence lifetime imaging microscopy support increased stabilization of enzyme–substrate complexes by all five FAD mutations. These findings provide further support for the stalled complex hypothesis, highlighting that FAD mutations impair γ-secretase function by promoting the accumulation of stalled enzyme–substrate complexes. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by multifactorial pathogenesis, including oxidative stress, cholinergic dysfunction, β-amyloid (Aβ) aggregation, and neuroinflammation. In this study, we investigated the neuroprotective potential of the Pheka capsule (PC) formula, a traditional Thai polyherbal medicine comprising Oroxylum indicum (OI), Zingiber officinale (ZO), and Boesenbergia rotunda (BR). Phytochemical analysis by HPLC confirmed the presence of key bioactive compounds including baicalein, baicalin, oroxylin A, 6-gingerol, 6-shogaol, pinocembrin, and pinostrobin. The PC formula exhibited strong antioxidant activity, highly selective butyrylcholinesterase (BChE) inhibition with a selectivity index (SI) of BChE > 20, suppression of Aβ aggregation, and protection against H₂O₂-induced neuronal damage in vitro. Network pharmacology analysis identified multiple AD-relevant targets and pathways, including APP, GSK3B, CASP3, GAPDH, PTGS2, and PPARG, implicating the PC formula in modulating oxidative stress, apoptosis, and inflammation. Notably, OI emerged as the primary contributor to the formula’s multitargeted actions. These findings support the therapeutic potential of the PC formula as a multitarget agent for AD, aligning with the growing interest in polypharmacological strategies for complex neurodegenerative diseases. Further in vivo and clinical studies are warranted to confirm its efficacy and safety. Full article

This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5–400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications. Full article

Alzheimer’s disease (AD) is a chronic and complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and irreversible impairment of brain functions. The etiology of AD is multifactorial, involving a complex interplay of genetic, environmental, and physiological factors, including the aggregation of amyloid-β (Aβ) and oxidative stress (OS). The role of OS in AD pathogenesis is of particular significance, given that an imbalance between oxidants and antioxidants promotes cellular damage, exacerbates Aβ deposition, and leads to cognitive deterioration. Despite extensive research, current therapeutic strategies have largely failed, likely due to the use of single-target drugs unable to halt the multifactorial progression of the disease. In this study, we investigated the synergistic therapeutic effect of plant-derived bioactive compounds Withanone, Apigenin, Bacoside A, Baicalin, and Thymoquinone in combination with N,N-Dimethyltryptamine (NN-DMT), a psychedelic molecule. We used a transgenic Caenorhabditis elegans model to assess the behavioral and molecular outcomes following compound exposure. Motility assays, thioflavin S staining, and survival assays under oxidative stress were employed to evaluate the treatment efficacy. The results of the behavioral and molecular analyses indicated that the combination therapy exhibited a higher efficacy than the monotherapies, leading to a significant reduction in age-related motility defects in the AD model. Furthermore, the combination treatment substantially reduced Aβ plaque burden, enhanced survival following OS insult, and demonstrated a synergistic effect in mitigating AD-related hallmarks. Taken together, these findings support the potential of combining NN-DMT with specific bioactive compounds as a promising multi-target therapeutic approach for AD. Full article

Background: Alzheimer’s disease (AD), a neurodegenerative disorder characterized by cognitive decline, has been linked to systemic inflammation. Periodontal disease (PD), a chronic inflammatory condition, may contribute to neurodegeneration via microbial dysbiosis and inflammatory pathways. This systematic review explores the potential association between PD and AD, emphasizing microbial and systemic mechanisms. Materials and Methods: Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science for studies published between 2015 and 2024. The boolean keywords “Alzheimer” AND “parodont*” were used. The inclusion criteria focused on human studies evaluating salivary and blood biomarkers, as well as periodontal therapies. Data extraction adhered to the PICO framework, assessing study design, outcomes, and quality using the ROBINS-I tool (original 2016 version), as provided by the Cochrane Bias Methods Group. Results: Out of the 1244 articles screened, 19 studies met the inclusion criteria. Evidence indicates that periodontal pathogens, such as Porphyromonas gingivalis, promote neuroinflammation, amyloid-β aggregation, and brain atrophy. Elevated inflammatory markers and oral dysbiosis correlated with increased AD risk. Periodontal treatment demonstrated benefits in reducing systemic inflammation and stabilizing cognitive decline. Conclusion: The findings suggest a strong link between PD and AD through systemic inflammation and microbial invasion. Maintaining oral health may serve as a preventive strategy against cognitive decline, underscoring the need for integrated medical–dental care and further longitudinal research. Full article

Sleep is essential for physical and mental health, playing a critical role in memory consolidation, behavioral stability, and the regulation of immune and metabolic functions. The incidence of sleep disorders, particularly sleep deprivation (SD), increases with age and is prevalent in neurodegenerative and psychiatric disorders such as Alzheimer’s disease (AD). Nearly 40% of AD patients experience significant chronic sleep impairments. The clinical distinction between late-life sleep disorders and AD is often challenging due to overlapping symptoms, including cognitive decline and behavioral impairments. Although the exact causal relationship between SD and AD remains complex and multifaceted, strong evidence suggests a bidirectional link, with AD patients frequently exhibiting disrupted sleep architecture, reduced slow-wave activity, and shorter total sleep duration. On a pathophysiological level, SD contributes to neuroinflammation, amyloid-β plaque deposition, and tau tangles, which are key features of AD. Current treatments, such as sedatives and antidepressants, often have limitations, including inconsistent efficacy, dependency risks, and poor long-term outcomes/recurrence, highlighting the need for safer and more effective alternatives. This review examines the interplay between SD and AD and proposes omega (n)-3 fatty acids (FAs) as a potential therapeutic intervention. Preclinical and clinical studies suggest that n-3 supplementation may improve sleep onset/quality, reduce neuroinflammation, support synaptic function, and decrease amyloid-β aggregation, thereby alleviating early AD-related neurological changes. Given their safety profile and neuroprotective effects, n-3 FAs represent a promising strategy for managing the comorbidity of sleep disorders in AD. Full article