Vaccination induces broadly neutralizing antibody precursors to HIV gp41.

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.

Structural basis of flagellar motility regulation by the MogR repressor and the GmaR antirepressor in Listeria monocytogenes.

The pathogenic Listeria monocytogenes bacterium produces the flagellum as a locomotive organelle at or below 30°C outside the host, but it halts flagellar expression at 37°C inside the human host to evade the flagellum-induced immune response. Listeria monocytogenes GmaR is a thermosensor protein that coordinates flagellar expression by binding the master transcriptional repressor of flagellar genes (MogR) in a temperature-responsive manner. To understand the regulatory mechanism whereby GmaR exerts the antirepression activity on flagellar expression, we performed structural and mutational analyses of the GmaR-MogR system. At or below 30°C, GmaR exists as a functional monomer and forms a circularly enclosed multidomain structure via an interdomain interaction. GmaR in this conformation recognizes MogR using the C-terminal antirepressor domain in a unique dual binding mode and mediates the antirepressor function through direct competition and spatial restraint mechanisms. Surprisingly, at 37°C, GmaR rapidly forms autologous aggregates that are deficient in MogR neutralization capabilities.

Cholesterol profiling reveals 7ß-hydroxycholesterol as a pathologically relevant peripheral biomarker of Alzheimer's disease.

AIM: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers. METHODS: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7ß-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment. RESULTS: The serum levels of several metabolites, including 7ß-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7ß-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7ß-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7ß-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1ß, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7ß-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively. CONCLUSIONS: Our results suggest that 7ß-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7ß-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.

Hexameric structure of the flagellar master regulator FlhDC from Cupriavidus necator and its interaction with flagellar promoter DNA.

Bacterial flagella are assembled with ∼30 different proteins in a defined order via diverse regulatory systems. In gram-negative bacteria from the Gammaproteobacteria and Betaproteobacteria classes, the transcription of flagellar genes is strictly controlled by the master regulator FlhDC. In Gammaproteobacteria species, the FlhDC complex has been shown to activate flagellar expression by directly interacting with the promoter region in flagellar genes. To obtain the DNA-binding mechanism of FlhDC and determine the conserved and distinct structural features of Betaproteobacteria and Gammaproteobacteria FlhDCs that are necessary for their functions, we determined the crystal structure of Betaproteobacteria Cupriavidus necator FlhDC (cnFlhDC) and biochemically analyzed its DNA-binding capacity. cnFlhDC specifically recognized the promoter DNA of the class II flagellar genes flgB and flhB. cnFlhDC adopts a ring-like heterohexameric structure (cnFlhD4C2) and harbors two Zn-Cys clusters, as observed for Gammaproteobacteria Escherichia coli FlhDC (ecFlhDC). The cnFlhDC structure exhibits positively charged surfaces across two FlhDC subunits as a putative DNA-binding site. Noticeably, the positive patch of cnFlhDC is continuous, in contrast to the separated patches of ecFlhDC. Moreover, the ternary intersection of cnFlhD4C2 behind the Zn-Cys cluster forms a unique protruding neutral structure, which is replaced with a charged cavity in the ecFlhDC structure.

Structural analysis of carboxyspermidine dehydrogenase from Helicobacter pylori.

Spermidine is a cationic polyamine that plays key roles in diverse biological processes, including biofilm formation and cell viability in bacteria. In some human gastrointestinal bacteria, such as Helicobacter pylori and Campylobacter jejuni, spermidine is biosynthesized using carboxyspermidine dehydrogenase (CASDH) and carboxyspermidine decarboxylase through an alternative pathway rather than the classical pathway found in most bacteria and eukaryotes. CASDH condenses putrescine and aspartate ß-semialdehyde into carboxyspermidine in an NADPH-dependent manner. Because structural information on CASDH is not available, the exact enzymatic mechanism of CASDH has not been elucidated. To reveal the structural features of CASDH required for cofactor and substrate recruitment, we determined the crystal structures of the H. pylori CASDH protein alone and in complex with NADP. CASDH consists of three domains (D1, D2, and D3) and assembles into a homodimer exclusively using the D3 domain. The CASDH structure harbors a dent between the D1 and D3 domains. The NADP cofactor is inserted into the interdomain dent and induces structural rearrangements in CASDH, including dent closure and local structural changes in the D1 and D3 domains. A comparative analysis suggests that the substrate of CASDH binds in a cavity near the nicotinamide moiety of NADPH for the condensation reaction.

Crystal structure of the antibiotic- and nitrite-responsive histidine kinase VbrK sensor domain from Vibrio rotiferianus.

Vibrio species are prevalent in the aquatic environments and can infect humans and aquatic organisms. Vibrio parahaemolyticus counteracts ß-lactam antibiotics and enhances virulence using a regulation mechanism mediated by a two-component regulatory system (TCS) consisting of the VbrK histidine kinase and the VbrR response regulator. The periplasmic sensor domain of VbrK (VbrKSD) detects ß-lactam antibiotics or undergoes S-nitrosylation in response to host nitrites. Although V. parahaemolyticus VbrKSD (vpVbrKSD) has recently been characterized through structural studies, it is unclear whether its structural features that are indispensable for biological functions are conserved in other VbrK orthologs. To structurally define the functionally critical regions of VbrK and address the structural dynamics of VbrK, we determined the crystal structures of Vibrio rotiferianus VbrKSD (vrVbrKSD) in two crystal forms and performed a comparative analysis of diverse VbrK structures. vrVbrKSD folds into a curved rod-shaped two-domain structure as observed in vpVbrKSD. The membrane-distal end of the vrVbrKSD structure, including the α3 helix and its neighboring loops, harbors both S-nitrosylation and antibiotic-sensing sites and displays high structural flexibility and diversity. Noticeably, the distal end is partially stabilized by a disulfide bond, which is formed by the cysteine residue that is S-nitrosylated in response to nitrite. Therefore, the distal end of VbrKSD plays a key role in initiating the VbrK-VbrR TCS pathway activation, and it is involved in the nitrosylation-mediated regulation of the structural dynamics of VbrK.

Structural analysis of the activation and DNA interactions of the response regulator VbrR from Vibrio parahaemolyticus.

VbrK and VbrR from the gastroenteritis-causing Vibrio parahaemolyticus are a histidine kinase and response regulator, respectively, that constitute a two-component regulatory system. VbrK responds to ß-lactam antibiotics or nitrate and activates VbrR via phosphorylation. Consequently, VbrR transcriptionally regulates the expression of ß-lactamase and ExsC and contributes to the survival or virulence of V. parahaemolyticus. Due to the unavailability of the VbrR structure, it remains unclear how VbrR is activated via its N-terminal receiver domain (RD) and recognizes dsDNA via its C-terminal DNA-binding domain (DBD). To reveal the mechanism underlying VbrR-mediated activation, we generated the phosphomimetic protein (VbrRRD-D51E) of the VbrR RD by replacing the D51 residue at the phosphorylation site with glutamate. VbrRRD-D51E exhibits a ß7α5 structure rather than the typical ß5α5 structure because it contains a unique two-stranded ß-sheet. The VbrRRD-D51E structure represents an active state in which the D51E residue interacts with the T78 residue. As a result, the Y97 residue adopts an inward conformation, allowing VbrRRD-D51E to dimerize using the α4-ß5-α5 face. These activation events are facilitated by a VbrR-specific residue, R52. Further structural study demonstrated that the VbrR DBD adopts a ß-strand-decorated three-helix structure. Based on a comparative structural study, we propose that VbrR recognizes dsDNA by inserting the α8 helix into the major groove of dsDNA and interacting with the minor groove of dsDNA via the ß11-ß12 region. Our findings will provide a new avenue for development of new antibacterial drugs for treating V. parahaemolyticus infections.

Structural analysis of the sensor domain of the ß-lactam antibiotic receptor VbrK from Vibrio parahaemolyticus.

Bacteria express ß-lactamase to counteract the bactericidal effects of ß-lactam antibiotics, which are the most widely employed antibacterial drugs. In gram-negative bacteria, the expression of ß-lactamase is generally regulated in response to the muropeptide that is generated from the peptidoglycan of the cell wall during ß-lactam antibiotic challenge. The direct regulation of ß-lactamase expression by ß-lactams was recently reported in Vibrio parahaemolyticus, and this regulation is mediated by a two-component regulatory system that consists of the histidine kinase VbrK and the response regulator VbrR. VbrK directly recognizes ß-lactam antibiotics using the periplasmic sensor domain (VbrKSD), a PF11884 Pfam family member, and it delivers the ß-lactam signal to VbrR to induce the transcription of the ß-lactamase gene. To determine the structural features of VbrKSD as the prototype of the PF11884 family and provide insights into the ß-lactam antibiotic-binding mode of VbrKSD, we determined the crystal structure of VbrKSD at 1.65 Å resolution. VbrKSD folds into a unique curved rod-like structure that has not been previously reported in other families. VbrKSD consists of two domains (D1 and D2). The D1 domain contains two helix-decorated ß-sheets, and the D2 domain adopts a helix-rich structure. VbrKSD features two terminal disulfide bonds, which would be the canonical property of the PF11884 family. In the VbrKSD structure, the L82 residue, which was previously shown to play a key role in ß-lactam antibiotic recognition, forms a pocket along with its neighboring hydrophobic or positively charged residues.

Structural basis of serum albumin recognition by SL335, an antibody Fab extending the serum half-life of protein therapeutics.

Human serum albumin (HSA) has been used to extend the serum half-lives of various protein therapeutics through genetic fusion because HSA exhibits an exceptionally long circulation time as a result of neonatal Fc receptor (FcRn)-mediated recycling. As another serum half-life extender, the human antibody Fab SL335 that strongly binds HSA was developed. When SL335 was fused to a protein therapeutic, SL335 was shown to prolong the half-life of the drug. Despite the significance of SL335-HSA binding in the extension of drug circulation time, it remains unclear how SL335 interacts with HSA at a molecular structural level. To reveal the structural basis of HSA recognition by SL335, we determined the crystal structure of the SL335-HSA complex at a resolution of 2.95 Å. SL335 binds HSA at a 1:1 stoichiometry. SL335 uses the exposed loops of its heavy and light chains to specifically recognize the IIa and IIb subdomains of HSA. The SL335 epitope is located on the opposite side of the FcRn-binding site and does not overlap with it, suggesting that SL335 extends the serum half-lives of itself and its fusion partner through an FcRn-dependent recycling mechanism.

Crystal structure of the flagellar cap protein FliD from Bdellovibrio bacteriovorus.

Bdellovibrio bacteriovorus is a predator bacterial species of the Deltaproteobacteria class that requires flagellum-mediated motility to initiate the parasitization of other gram-negative bacteria. The flagellum is capped by FliD, which polymerizes flagellin into a flagellar filament. FliD has been reported to function as a species-specific oligomer, such as a tetramer, a pentamer, or a hexamer, in members of the Gammaproteobacteria class. However, the oligomeric state and structural features of FliD from bacterial species outside the Gammaproteobacteria class are unknown. Based on structural and biochemical analyses, we report here that B. bacteriovorus FliD (bbFliD) forms a tetramer. bbFliD tetramerizes in a circular head-to-tail arrangement by inserting the D2 domain of one subunit into the concave surface of the second subunit generated between the D2 and D3 domains as observed in Serratia marcescens FliD. However, bbFliD adopts a more compact and flat oligomeric structure, which exhibits a more extended tetramerization interface flanked by two additional surfaces due to different intersubunit and interdomain organizations as well as an elongated loop. In conclusion, FliD from B. bacteriovorus, which belongs to the Deltaproteobacteria class, also produces a tetramer similar to FliD from Gammaproteobacterial species but adopts a unique species-specific oligomeric structure.

Structural analysis of the flagellar capping protein FliD from Helicobacter pylori.

Helicobacter pylori is a pathogenic flagellated bacterium that infects the gastroduodenal mucosa and causes peptic ulcers in humans. FliD caps the distal end of the flagellar filament and is essential in filament growth. Moreover, FliD has been studied to diagnose and prevent H. pylori infection. Here, we report structure-based molecular studies of H. pylori FliD (hpFliD). A crystal structure of hpFliD at 2.6 Šresolution presents a four-domain (D2-D5) structure, where the D3 domain forms a central platform surrounded by the other three domains (D2, D4, and D5). hpFliD domains D2 and D3 structurally resemble those of FliD orthologs, whereas the D4 and D5 domains are exclusive to hpFliD. Moreover, our ELISA analysis using anti-H. pylori antibodies demonstrated that the hpFliD-specific D4 and D5 domains are highly antigenic compared to the D2 and D3 domains. Collectively, our structural and serological analyses underscore the structural role of hpFliD domains and provide a molecular basis for vaccine and diagnosis development.

Particulate matter increases beta-amyloid and activated glial cells in hippocampal tissues of transgenic Alzheimer's mouse: Involvement of PARP-1.

Exposure to air pollutants, such as particulate matter (PM), has been implicated in neurodegenerative disorders including Alzheimer's disease (AD). However, direct effects of PM on production of ß-amyloid (Aß), a key pathogenic molecule in AD, and its underlying mechanism are still elusive. Given PM's potential to induce oxidative stress in other tissues, we hypothesized that poly(ADP-ribose) polymerase (PARP-1) might be involved in PM-induced neurotoxicity. To address this, we used an ex vivo model of AD, the organotypic hippocampal slice tissue culture from old (12-14 months-of-age) triple transgenic 3xTg-AD mice. First, we observed that fine PM (aerodynamic diameter < 4 µm) can dose-dependently activate PARP-1 and decrease NAD+ levels in Neuro2A cells. PARP-1 activation did occur under concentrations of PM which did not affect cell viability. Next, we observed that direct treatment of PM increased Aß levels and activated glial cells in the ex vivo hippocampal tissues of 3xTg-AD mice. PM-induced glial activation was most prominent in CA1 region of the hippocampal tissue. Notably, we found that pharmacological inhibition of PARP-1 reversed both PM-induced Aß increase and glial activation, arguing the possible involvement of PARP-1 in PM-induced AD pathogenesis. Our findings suggest that PARP-1 might be a potential molecular target, responsible for mediating negative effects of PM on the brain. Modulating PARP-1 activity could be a promising approach to prevent or alleviate PM-related environmental neurotoxicity which could initiate AD pathogenesis.

Tetrameric structure of the flagellar cap protein FliD from Serratia marcescens.

Bacterial motility is provided by the flagellum. FliD is located at the distal end of the flagellum and plays a key role in the insertion of each flagellin protein at the growing tip of the flagellar filament. Because FliD functions as an oligomer, the determination of the oligomeric state of FliD is critical to understanding the molecular mechanism of FliD-mediated flagellar growth. FliD has been shown to adopt a pentameric or a hexameric structure depending on the bacterial species. Here, we report another distinct oligomeric form of FliD based on structural and biochemical studies. The crystal structures of the D2 and D3 domains of Serratia marcescens FliD (smFliD) were determined in two crystal forms and together revealed that smFliD assembles into a tetrameric architecture that resembles a four-pointed star plate. smFliD tetramerization was also confirmed in solution by cross-linking experiments. Although smFliD oligomerizes in a head-to-tail orientation using a common primary binding interface between the D2 and D3' domains (the prime denotes the second subunit in the oligomer) similarly to other FliD orthologs, the smFliD tetramer diverges to present a unique secondary D2-D2' binding interface. Our structure-based comparative analysis of FliD suggests that bacteria have developed diverse species-specific oligomeric forms of FliD that range from tetramers to hexamers for flagellar growth.

First detection of Bandavirus dabieense in ticks collected from migratory birds in the Republic of Korea.

The causative agent of severe fever with thrombocytopenia syndrome (SFTS) is Bandavirus dabieense, an emerging tick-borne zoonotic pathogen. Migratory birds have often been suggested as potential carriers of ticks that can transmit Bandavirus dabieense; however, their role remains unclear. The Republic of Korea (ROK) holds an important position as a stopover on the East Asian-Australasian Flyway. The present study aimed to investigate the potential involvement of migratory birds in the transmission of the SFTS virus (SFTSV) in the ROK. A total of 4,497 ticks were collected across various regions, including Heuksando and Daecheongdo, in the ROK, from bird migration seasons in 2022 and 2023. Genetic analysis of the SFTSV was performed for 96 ticks collected from 20 different species of migratory birds. Polymerase chain reaction (PCR) fragments of SFTSV were detected in one Haemaphysalis concinna nymph collected from a Black-faced Bunting (Emberiza spodocephala) and one Ixodes turdus nymph collected from an Olive-backed Pipit (Anthus hodgsoni) on Daecheongdo and Heuksando, respectively, during their northward migration in two spring seasons. This finding suggests that migratory birds can be considered as possible carriers and long-distance dispersers of ticks and associated tick-borne diseases. This study highlights the importance of clarifying the role and impact of migratory birds in the rapid expansion of tick-borne diseases, facilitating enhanced preparedness and the development of mitigation measures against emerging SFTS across and beyond East Asia.

Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer's model mice.

Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer's disease (AD), also known as "type 3 diabetes". Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, ß-amyloid oligomers, plaques, phosphorylated tau, and GSK3ß expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.

Relationship Between Adipokines, Cognition, and Brain Structures in Old Age Depending on Obesity.

BACKGROUND: Adipokines such as leptin and adiponectin are associated with cognitive function. Although adiposity crucially affects adipokine levels, it remains unclear whether the relationship between adipokines and cognition is influenced by obesity. METHODS: We enrolled 171 participants and divided them into participants with obesity and without obesity to explore the effect of obesity on the relationship between adipokines and cognition. In addition to plasma levels of leptin and adiponectin, multidomain cognitive functions and brain structures were assessed using neuropsychological testing and magnetic resonance imaging. Association between levels of these adipokines and Alzheimer's disease (AD) was then assessed by logistic regression. RESULTS: We found that cognitive function was negatively associated with leptin levels and leptin-to-adiponectin ratio (LAR). Such correlations between leptin and cognitive domains were prominent in participants with obesity but were not observed in those without obesity. Leptin levels were associated with lower hippocampal volumes in participants with obesity. A significant interaction of leptin and obesity was found mostly in the medial temporal lobe. Both leptin and LAR were positively associated with insulin resistance and inflammation markers in all participants. Of note, LAR was associated with a higher risk of AD after adjusting for demographic variables, Apolipoprotein E genotype, and body mass index. CONCLUSIONS: Obesity might be a factor that determines how adipokines affect brain structure and cognition. Leptin resistance might influence the relationship between adipokines and cognition. In addition, LAR rather than each adipokine levels alone may be a better indicator of AD risk in older adults with metabolic stress.

Milnacipran Has an Antihyperalgesic Effect on Cisplatin-Induced Neuropathy.

(1) Background: Milnacipran is a typical serotonin-norepinephrine reuptake inhibitor and has been shown to have analgesic effects in several pain models. However, its antihyperalgesic effect in cisplatin-induced neuropathy remains unknown. We examined the effects of intraperitoneal (IP) milnacipran on allodynia in cisplatin-induced peripheral neuropathic mice. (2) Methods: Peripheral neuropathy was induced by injecting cisplatin (2.3 mg/kg/day, IP) six times, on every other day. Saline or milnacipran (10, 30, 50 mg/kg, IP) were then administered to the neuropathic mice. We examined mechanical allodynia using von Frey hairs at preadministration and at 30, 60, 90, 120, 180, 240 min and 24 h after drug administration. We also measured the dorsal root ganglion (DRG) activating transcription factor 3 (ATF3) to confirm the analgesic effects of milnacipran. (3) Results: For the milnacipran groups, the decreased paw withdrawal thresholds to mechanical stimuli were significantly reversed when compared to the preadministration values and the values in the saline-injected control group (p < 0.0001). Milnacipran administration to cisplatin-induced peripheral neuropathic mice resulted in a significant suppression of neuronal ATF3 activation (p < 0.01). (4) Conclusions: Milnacipran given via IP injection attenuates mechanical allodynia in mouse models of cisplatin-induced poly-neuropathic pain. These effects were confirmed by significant suppression of neuronal ATF3 activation in the DRG.

Plasma adiponectin levels predict cognitive decline and cortical thinning in mild cognitive impairment with beta-amyloid pathology.

BACKGROUND: Blood adiponectin and leptin are adipokines that emerged as potential biomarkers for predicting Alzheimer's disease (AD) owing to their strong connection with obesity. Although obesity affects the relation between beta-amyloid (Aß) aggregation and cognitive decline, the longitudinal interactive effect of adipokines and Aß on cognition and brain structures in humans remains unexplored. Hence, we investigated whether plasma levels of adiponectin and leptin are associated with future cognitive decline and cortical thinning across Aß conditions (Aß [+] and Aß [-]) in individuals with mild cognitive impairment (MCI). METHODS: Of 156 participants with MCI from the longitudinal cohort study of Alzheimer's Disease Neuroimaging Initiative (ADNI), 31 were Aß (-) and 125 were Aß (+) as determined by CSF analysis. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and the thickness of the parahippocampal and entorhinal cortices were used to evaluate cognition and brain structure, respectively. After stratifying groups by Aß conditions, the association of cognitive and brain structural changes with baseline plasma levels of adiponectin and leptin was examined. RESULTS: Of the total 156 participants, 51 were women (32.7%). The mean age of participants was 74.5 (standard deviation 7.57), and the mean follow-up period was 54.3 months, without a difference between the Aß (+) and (-) groups. After adjustment for confounders, higher plasma adiponectin levels were associated with a faster increase in ADAS-Cog scores, indicating faster cognitive decline under the Aß (+) condition (beta = 0.224, p = 0.018). Likewise, participants with higher plasma adiponectin presented faster cortical thinning in the bilateral parahippocampal cortices under the Aß (+) condition (beta = - 0.004, p = 0.012 for the right side; beta = - 0.004, p = 0.025 for the left side). Interestingly, plasma adiponectin levels were not associated with longitudinal ADAS-Cog scores or cortical thickness in the Aß (-) condition. Plasma leptin levels were not predictive of cognition or cortical thickness regardless of Aß status. CONCLUSION: Plasma adiponectin can be a potential biomarker for predicting the speed of AD progression in individuals with Aß (+) MCI.

Loss of association between plasma irisin levels and cognition in Alzheimer's disease.

BACKGROUND: Irisin, an exercise-induced myokine, has been shown to have beneficial effects on cognitive and metabolic functions. However, previous studies assessing the levels of circulating irisin in patients with Alzheimer's disease (AD) or diabetes mellitus (DM) have provided inconsistent results. This suggests that the normal physiological action of irisin may be altered by disease-associated pathological conditions in target organs. OBJECTIVE: To investigate the association of plasma levels of irisin with cognition and brain structures according to the presence or absence of AD and DM. METHODS: Plasma levels of irisin, multi-domain cognition, and volumes of relevant brain regions were assessed using enzyme-linked immunoassay, neuropsychological test, and magnetic resonance imaging, respectively. We classified 107 participants by cognitive (cognitively normal [CN, n = 23], mild cognitive impairment [MCI, n = 49], and AD [n = 35]) and metabolic (non-DM [n = 75] and DM [n = 32]) states. RESULTS: Disease state-stratified multiple regression analyses showed that plasma levels of irisin were positively associated with cognition only in participants without AD (CN plus MCI). By contrast, in participants with AD, these associations lost significance, and furthermore, higher levels of irisin indicated smaller hippocampal, superior temporal, and inferior frontal volumes. The association between plasma irisin levels and cognition was not affected by the presence of DM. Consistently, moderation analysis revealed that the relationship between plasma irisin levels and cognition or brain structures was significantly modified by the presence of AD, not that of DM. CONCLUSION: Our findings suggest that the beneficial actions of circulating irisin on cognition may be attenuated by AD-induced pathological conditions in the brain.