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bioRxiv2017

Effect of 40Gy irradiation on the ultrastructure, biochemistry, morphology and cytology during spermatogenesis in the southern green stink bug Nezara viridula (Hemiptera: Pentatomidae)

A study on the Nezara viridula male gonad cells was undertaken to compare normal development and development of insect cells after irradiation of 4th instar nymphs with a dose of 40 Gray. Visually, morphologically, biochemically and cytologically the insects were not all uniformly affected by the radiation. In all aspects of development there was a range from severely affected to nearly normal. Irradiated insects appeared to move slowly and were unable to mate with non-irradiated females. The testes of the males varied from bright orange to grey in colour and all were smaller in size than non-irradiated testes. The ultrastructure of the developing sperm showed abnormalities the axonemes, the mitochrondrial derivatives, nebenkern and centrioles. Cytochemically, the main difference observed was the presence of granules heavily stained with acid phosphatase in between mitochrondrial derivatives. The chromosomes of these irradiated insects were highly fragmented. Although a few sperm in irradiated insects appeared normal no progeny were produced as insect did not mate. The sterile insect technique (SIT) requires a balance between the effective radiation dose to achieve partial or full sterility, while maintaining physical fitness. The observation that abnormalities varied from almost none to severe at 40Gy could help the development of SIT for control of N. viridula and other Pentatomidae.

developmental biology↗

bioRxiv2017

Specialized plant biochemistry drives gene clustering in fungi

The fitness and evolution of both prokaryotes and eukaryotes are affected by the organization of their genomes. In particular, the physical clustering of functionally related genes can facilitate coordinated gene expression and can prevent the breakup of co-adapted alleles in recombining populations. While clustering may thus result from selection for phenotype optimization and persistence, the extent to which eukaryotic gene organization in particular is driven by specific environmental selection pressures has rarely been systematically explored. Here, we investigated the genetic architecture of fungal genes involved in the degradation of phenylpropanoids, a class of plant-produced secondary metabolites that mediate many ecological interactions between plants and fungi. Using a novel gene cluster detection method, we identified over one thousand gene clusters, as well as many conserved combinations of clusters, in a phylogenetically and ecologically diverse set of fungal genomes. We demonstrate that congruence in gene organization over small spatial scales in fungal genomes is often associated with similarities in ecological lifestyle. Additionally, we find that while clusters are often structured as independent modules with little overlap in content, certain gene families merge multiple modules in a common network, suggesting they are important components of phenylpropanoid degradation strategies. Together, our results suggest that phenylpropanoids have repeatedly selected for gene clustering in fungi, and highlight the interplay between gene organization and ecological evolution in this ancient eukaryotic lineage.

genomics↗

bioRxiv2019

Serum biochemistry suggests grey squirrels (Sciurus carolinensis) have poorer physiological condition in urban settings

Human food waste in cities presents urban wildlife with predictable, easily accessible high-calorie food sources, but this can be both beneficial and harmful for individual health. We analyzed body condition and serum chemistry (electrolyte levels, markers of kidney and liver function, protein, glucose, and cholesterol) in an urban and rural population of eastern grey squirrels (Sciurus carolinensis) to assess whether proximity to the human food waste that is associated with urban habitats had ill effects on health. We found no differences in body condition between habitats and no evidence of malnutrition at either site. However, urban squirrels had higher blood glucose, lower potassium, phosphorus, chloride, and albumin:globulin ratios. These results align with previous findings of increased dietary sugar in cities, and suggest that urban populations of grey squirrels are under greater environmental stress than rural populations.

physiology↗

bioRxiv2020

The Roles of Space and Stochasticity in Computational Simulations of Cellular Biochemistry: Quantitative Analysis and Qualitative Insights

Most of the fascinating phenomena studied in cell biology emerge from interactions among highly organized multi-molecular structures and rapidly propagating molecular signals embedded into complex and frequently dynamic cellular morphologies. For the exploration of such systems, computational simulation has proved to be an invaluable tool, and many researchers in this field have developed sophisticated computational models for application to specific cell biological questions. However it is often difficult to reconcile conflicting computational results that use different simulation approaches (for example partial differential equations versus particle-based stochastic methods) to describe the same phenomenon. Moreover, the details of the computational implementation of any particular algorithm may give rise to quantitatively or even qualitatively different results for the same set of starting assumptions and parameters. In an effort to address this issue systematically, we have defined a series of computational test cases ranging from very simple (bimolecular binding in solution) to moderately complex (spatial and temporal oscillations generated by proteins binding to membranes) that represent building blocks for comprehensive three-dimensional models of cellular function. Having used two or more distinct computational approaches to solve each of these test cases with consistent parameter sets, we generally find modest but measurable differences in the solutions of the same problem, and a few cases where significant deviations arise. We discuss the strengths and limitations of commonly used computational approaches for exploring cell biological questions and provide a framework for decision-making by researchers wishing to develop new models for cell biology. As computational power and speed continue to increase at a remarkable rate, the dream of a fully comprehensive computational model of a living cell may be drawing closer to reality, but our analysis demonstrates that it will be crucial to evaluate the accuracy of such models critically and systematically.

systems biology↗

bioRxiv2021

Widespread bacterial protein flavinylation in functionally distinct extracytosolic redox biochemistries

Disparate redox activities that take place beyond the bounds of the prokaryotic cell cytosol must connect to membrane or cytosolic electron pools. Proteins post-translationally flavinylated by the enzyme ApbE mediate electron transfer in several characterized extracytosolic redox systems but the breadth of functions of this modification remains unknown. Here we present a comprehensive bioinformatic analysis of 31,910 prokaryotic genomes that provides evidence of extracytosolic ApbEs within ~50% of bacteria and the involvement of flavinylation in numerous uncharacterized biochemical processes. By mining flavinylation-associated gene clusters, we identify five protein classes responsible for transmembrane electron transfer and two domains of unknown function (DUF2271 and DUF3570) that are flavinylated by ApbE. We observe flavinylation/iron transporter gene colocalization patterns that implicate functions in iron reduction and assimilation. We find associations with characterized and uncharacterized respiratory oxidoreductases that highlight roles of flavinylation in respiratory electron transport chains. Finally, we identify interspecies gene cluster variability consistent with flavinylation/cytochrome functional redundancies and discover a class of "multi-flavinylated proteins'' that may resemble multiheme cytochromes in facilitating longer distance electron transfer. These findings provide key mechanistic insight into an important facet of bacterial physiology and establish flavinylation as a functionally diverse mediator of extracytosolic electron transfer. Impact StatementBioinformatic and biochemical studies find that covalently bound flavins are common and participate in wide-ranging extracytosolic redox activities throughout bacterial life.

microbiology↗

bioRxiv2021

Mesophyll conductance response to short-term changes in pCO2 is related to leaf anatomy and biochemistry in diverse C4 grasses

O_LIMesophyll CO2 conductance (gm) in C3 species responds to short-term (minutes) changes in environment potentially due to changes in some leaf anatomical and biochemical properties and due to measurement artifacts. Compared to C3 species, there is less information about gm responses to short-term changes in environment conditions like pCO2 across diverse C4 species and the potential determinants of these responses. C_LIO_LIUsing 16 diverse C4 grasses we investigated the response of gm to short-term changes in CO2 and how this response related to the leaf anatomical and biochemical traits. C_LIO_LIFor all the measured C4-grasses gm increased as CO2 decreased; however, the percent change in gm varied (+13% to +250%) and significantly related to percent changes in leaf transpiration efficiency (TEi). The percent increase in gm was highest in grasses with thinner mesophyll cell walls and greater leaf nitrogen, activities of phosphoenolpyruvate carboxylase (PEPC), Rubisco and carbonic anhydrase, and a higher affinity of PEPC for bicarbonate. C_LIO_LIOur study demonstrates that CO2 response of gm varies greatly across diverse C4 grasses and identifies the key leaf anatomical and biochemical traits related to this variation. These findings have implications for improving C4 photosynthetic models, and in attempts to improve TEi through manipulation of gm. C_LI

plant biology↗

bioRxiv2021

Cell Wall Biochemistry Drives Pollen Tube Mechanics and Affects Growth Rate

Pollen tubes maintain cell wall integrity as they rapidly grow towards the ovule, yet need to rupture at a precise moment to release the sperm cells. This biomechanical balance is critical for fertilization and relies on the interplay between turgor pressure and cell wall rigidity. How cell wall composition affects its mechanical properties is, however, not well understood. In this study, we combine experimental and simulation techniques to determine key mechanical parameters using Arabidopsis cell wall mutants. We integrated cellular force microscopy with a Finite Element Method-based model to predict growth rates of different mutant pollen tubes. The Finite Element Method-based model allowed us to quantify the effects of cell wall mutations on the time-independent turgor pressure and cell wall elasticity, while cellular force microscopy enabled determination of time-dependent viscoelastic properties of the cell wall. This novel approach can be applied across biological systems and advances mechanical studies of cell and tissue morphogenesis.

systems biology↗

bioRxiv2022

Biochemistry and nanomechanical properties of human colon cells upon simvastatin, lovastatin and mevastatin supplementations - Raman imaging and AFM studies

One of the most important areas of medical science is oncology, which is responsible for both the diagnostics and treatment of cancer diseases. Over the years, there has been an intensive development of cancer diagnostics and treatment. This paper shows the comparison of normal (CCD-18Co) and cancerous (CaCo-2) cell lines of the human gastrointestinal tract on the basis of nanomechanical and biochemical properties in order to obtain information on the cancer biomarkers useful in oncological diagnostics. The research techniques used were: Atomic Force Microscopy and Raman spectroscopy and imaging. In addition, the studies included also the effect of the statins compounds: mevastatin, lovastatin and simvastatin and their influence on nanomechanical and biochemical changes of properties of cells tracking using AFM and Raman imaging techniques. The cytotoxicity of mevastatin and lovastatin was determined by using XTT tests.

cell biology↗

bioRxiv2022

Correlative SIP-FISH-SEM-Raman-NanoSIMS links identity, morphology, biochemistry, and physiology of environmental microbes

Microscopic and spectroscopic techniques are commonly applied to study microbial cells but are typically used on separate samples, resulting in population-level datasets that are integrated across different cells with little spatial resolution. To address this shortcoming, we developed a workflow that correlates several microscopic and spectroscopic techniques to generate an in-depth analysis of individual cells. By combining stable isotope probing (SIP), fluorescence in situ hybridization (FISH), scanning electron microscopy (SEM), confocal Raman microspectroscopy (Raman), and nano-scale secondary ion mass spectrometry (NanoSIMS), we illustrate how individual cells can be thoroughly interrogated to obtain information about their taxonomic identity, structure, physiology, and metabolic activity. Analysis of an artificial microbial community demonstrated that our correlative approach was able to resolve the activity of single cells using heavy water SIP in conjunction with Raman and/or NanoSIMS and establish their taxonomy and morphology using FISH and SEM. This workflow was then applied to a sample of yet uncultured multicellular magnetotactic bacteria (MMB). In addition to establishing their identity and activity, backscatter electron microscopy (BSE), NanoSIMS, and energy-dispersive X-ray spectroscopy (EDS) were employed to characterize the magnetosomes within the cells. By integrating these techniques, we demonstrate a cohesive approach to thoroughly study environmental microbes on a single cell level.

microbiology↗

bioRxiv2023

Impact of acute chlorpyrifos toxicity on the histology and biochemistry of the stomach, intestine, and muscle of the Anabas testudineus

Chlorpyrifos is classified as an organophosphorus pesticide that exhibits properties of being a broad-spectrum insecticide, acaricide, and nematicide. It is characterized by its ability to degrade quickly and its non-persistent nature. The current investigation involved the determination of the LC50 value of chlorpyrifos on A. testudineus. The computed LC50 values were found to be 11.59, 8.82, 6.30, and 3.82 ppm for exposure durations of 24, 48, 72, and 96 hours, respectively. The levels of protein and glycogen in the stomach, gut, and muscle of A. testudineus, which were subjected to a concentration of 3.82 ppm (LC50 96 hours) chlorpyrifos for a duration of 96 hours, exhibited a notable reduction when compared to the control group. The stomach sections of A. testudineus, when subjected to a concentration of 3.82 ppm chlorpyrifos for a duration of 96 hours, exhibited degeneration of the mucosa layer and necrosis of the mucosa epithelium. The histopathological examination of the intestine revealed several notable findings, including the presence of a disintegrating serosa, a significantly enlarged muscularis layer, and observable damage to both the circular muscle layer and submucosa. Additionally, evidence of necrosis was observed within the mucosa layer. The muscle tissue exhibited degeneration inside the muscle bundles, characterized by the presence of discrete regions of necrosis and the development of vacuoles within the muscle bundles. The results of this study demonstrate that chlorpyrifos exhibits a significant level of toxicity towards A. testudineus, and it is important to note that the absence of mortality does not guarantee the maintenance of physiological well-being in this particular fish species.

zoology↗

bioRxiv2024

Untargeted metabolomics reveals anion and organ-specific biochemistry of salinity tolerance in willow

1Willows can alleviate soil salinisation while generating sustainable feedstock for biorefinery, yet the metabolomic adaptations underlying their salt tolerance remain poorly understood. Testing two environmentally abundant salts, the response of Salix miyabeana was assessed after treatment with a moderate concentration of NaCl, and both moderate and high concentrations of Na2SO4 in a 12-week pot trial. Willows tolerated salts across all treatments (up to 9.1dS m-1 soil ECe), maintaining photosynthesis and biomass while selectively partitioning ions, confining Na+ to roots and accumulating Cl- and SO 2- in the canopy, and adapting to osmotic stress via reduced stomatal conductance. Untargeted LC-MS/MS captured over 5,000 putative compounds, characterising the baseline willow metabolome, including 278 core compounds constitutively produced across organs. Comparative statistical analyses revealed widespread metabolic reprogramming in response to soil salinity, altering 28% of the overall metabolome, and highlighting organ-tailored regulation. Comparing both salt forms at equimolar sodium, generalised salinity responses were limited to 3% of the metabolome, predominantly in roots. Anion-specific metabolomic responses were more extensive, with NaCl reducing carbohydrates and TCA intermediates, thereby exerting pressure on carbon and energy resources, alongside the accumulation of root structuring compounds, antioxidants flavonoids, and fatty acids. In contrast, Na2SO4 salinity triggered accumulation of sulphur-containing larger peptides, suggesting that excess sulphate incorporation leverage ion toxicity to produce specialized salt-tolerance associated metabolites. This high-depth picture of the willow metabolome underscores the importance of capturing plant adaptations to salt stress at organ-scale and considering ion-specific contributions to soil salinity.

plant biology↗

bioRxiv2024

Equity in Action: A Four-Year journey towards Gender Parity and Racial Diversity in Biochemistry Hiring

Recruitment of faculty members in academic departments shapes the department for decades in both research and teaching arenas. Having a diverse department is beneficial for undergraduate and graduate students as representation of underrepresented minority groups in the professoriate can inspire a greater diversity of students to pursue higher levels of education or research-focused careers. Increased diversity benefits research directly as diverse teams have been shown to have better ideas and outcomes. In 2020, our department had lower gender diversity than would be expected based on the pool of PhD students and post-doctoral fellows in Canada. Therefore, we altered our hiring process, primarily by redacting applications, for recruitment into entry-level tenure-track faculty positions. With this change in process, female hires increased from 17% in the previous ten years (5 hires) to 80% in the subsequent four years (5 hires) with no substantial change in hiring of racially diverse individuals (50% to 40%). Overall, combined with retirements, the percentage of female faculty in the department went from 25% to 50% and the percentage of racialized faculty went from 38% to 44%. The new hires have met or exceeded expectations of success with respect to grant funding and are on track to meet or exceed expectations for other metrics of success. Thus, our intervention was very successful in increasing the diversity of our department within a short timeframe. We believe that our experience could provide other departments with a template for making substantive change, even in the absence of internal expertise in the area. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/617211v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@164c310org.highwire.dtl.DTLVardef@42585borg.highwire.dtl.DTLVardef@1b6f6eaorg.highwire.dtl.DTLVardef@10ca067_HPS_FORMAT_FIGEXP M_FIG C_FIG

scientific communication and education↗

bioRxiv2025

Heterochromatin-based silencing of a foreign tandem repeat in Drosophila melanogaster shows unusual biochemistry and temperature sensitivity

Eukaryotic genomes are packaged into chromatin, a regulatory nucleoprotein assembly. Establishment, maintenance, and interconversion of chromatin states is required for correct patterns of gene expression, genome integrity, and survival. Transcriptionally repressive heterochromatin minimizes mobilization of transposable elements and limits expansion of other repetitive DNA, but mechanisms for recognition of the latter sequences are not well established. We previously demonstrated in Drosophila melanogaster that transcripts derived from 1360 and Invader4 transposon insertions can trigger local conversion of transcriptionally permissive euchromatin to heterochromatin through the piRNA system, but only in a subset of genomic locations near existing blocks of heterochromatin. Here we show that a ~9 kb tandem array of the 36-nucleotide lac operator (lacO) sequence of Escherichia coli can form ectopic heterochromatin at a similar subset of sites, resulting in variegating expression of an adjacent reporter gene. Heterochromatin Protein 1a (HP1a) and histone deacetylation are required for lacO repeat-induced silencing, but, contrasting with previously described Position Effect Variegation (PEV), we do not observe increased histone H3 lysine 9 methylation. Silencing is effective at 25{degrees}C and suppressed at 18{degrees}C (in contrast to canonical PEV, which is enhanced at 18{degrees}C), indicating involvement of a temperature-sensitive component. Temperature switching experiments show that lacO repeat-induced heterochromatin formation is reversible throughout larval development following an HP1a-dependent initiation step in the early embryo. We conclude that the Drosophila nucleus can recognize a completely foreign tandem repeat as a target for heterochromatin formation, and that the heterochromatin structure established is distinct from that of endogenous tandem arrays.

genetics↗

bioRxiv2025

Macrophage signaling and function are regulated by distinct sterol biochemistries

Membranes require continuous reorganization of lipid components, including sterols, to dynamically alter their rigidity to deform and bend during scission events which occur during fundamental cellular functions such as endocytosis. While diseases of cholesterol biosynthesis result in reduced cellular cholesterol and accumulation of precursor sterols, limited studies have addressed the intracellular consequences of disease-associated sterol changes on the ability of eukaryotic cellular membranes to function and signal normally. Here, we utilized bone marrow-derived macrophages (BMDMs) to investigate how altered sterol content impacts macrophage signaling and membrane function. Through pharmacological inhibition of cholesterol biosynthetic enzymes, reduced cholesterol and increased levels of disease-associated sterol intermediates coincided with reduced expression of cell surface proteins and impaired macropinocytosis. Macropinocytic activity was sensitive to both reduced plasma membrane cholesterol and sterols containing functional groups substituted for the C3 hydroxyl group. Transcriptomic analyses of cholesterol-inhibited BMDMs revealed alterations in immune and chemokine signaling pathways. Decreased cholesterol was also associated with dysregulated vesicular sorting pathways and elevated expression of endosomal/lysosomal markers. Disrupted endosome expression and impaired macropinocytosis was also observed in BMDMs from mouse models of the cholesterol biosynthesis disorder Smith-Lemli-Opitz syndrome (SLOS). Our findings detail an important connection between sterol imbalance, membrane dynamics, and immune cell function.

cell biology↗

bioRxiv2025

Dosa: A method to covalently barcode proteinsfor high throughput biochemistry

Deep mutational scanning couples a proteins activity to DNA sequencing for high throughput assessment of the effects of all single amino acid substitutions, but it largely uses indirect assays, like growth, as proxy for protein activity. Here, we covalently link variant proteins in vivo to an RNA barcode by fusing them to E. coli tRNA (m5U54) methyltransferase TrmA (E358Q), which forms a covalent bond with a tRNA stem-loop. Following cell lysis, variant proteins are separated in vitro according to their biochemical properties and identified by their barcodes. We use this method, Dosa, to analyze a large pool of FLAG epitope variants for binding to an anti-FLAG antibody, to profile the cleavage preferences of variants of enteropeptidase and human rhinovirus 3C protease, and to measure the solubility of several hundred A{beta}(1-42) variants. This method should be amenable to numerous biochemical assays with proteins produced in E. coli or mammalian cells.

genomics↗

bioRxiv2025

Fresh Paraformaldehyde Preserves Thrombus Biochemistry - An ATR-FTIR and PCA Investigation of Pulmonary Artery Thrombi

BackgroundBiochemical analyses of pulmonary embolism derived thrombi depend critically on fixative quality. ObjectiveTo quantify the impact of paraformaldehyde (PFA) shelf life on thrombus molecular integrity using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and time-of-flight secondary ion mass spectroscopy (SIMS) combined with principal component analysis. MethodsTen pulmonary artery thrombi were fixed in either aged PFA (6 months; n = 6) or freshly prepared 4% PFA (n = 4); an in-vitro plasma clot control received the same fresh PFA. Triplicate ATR-FTIR spectra (400-4000 cm-1) were collected and vector-normalized to the Amide I band. ToF-SIMS measurements were performed using a 30 keV Bi primary ion beam Fixative chemistry was assessed by the carbonyl absorbance at 1700 cm-1. ResultsFreshly fixed thrombi displayed narrow Amide I (~1650 cm-1) and Amide II (~1540 cm-1) bands with a higher signal-to-noise ratio (SNR; median 41.8) than aged-PFA samples (18.2; P < .01). Carbonyl absorbance at 1700 cm-1 was markedly higher in fresh PFA. Aged PFA introduces chemical variances of biological samples in low-mass molecule fragments. PCA showed clear separation of fresh versus aged specimens and alignment of fresh thrombi with plasma controls across spectral windows. ConclusionsPFA solutions older than three months markedly deteriorate thrombus biochemical fidelity. ATR-FTIR and ToF-SIMS offer a rapid quality-control assay prior to molecular analyses. Key pointsO_LIPFA stored [≥]3 months loses >70% of reactive aldehydes, yielding broad Amide envelopes, attenuated lipid bands and a two fold SNR drop. C_LIO_LIAged PFA introduces chemical variances of biological samples in low-mass molecule fragments. C_LIO_LIPCA of fingerprint, protein or lipid windows cleanly separates aged from fresh fixations (PC1 up to 80% variance). C_LIO_LIA rapid QC workflow (carbonyl absorbance [≥]0.25 a.u. plus PCA verification) safeguards molecular integrity irrespective of patient age, DVT history or clinical severity. C_LIO_LIAdopting this workflow will harmonise multi centre clot biorepositories and enhance the reproducibility of proteomic, lipidomic and imaging studies. C_LI

biophysics↗

bioRxiv2018

Multi omics comparison reveals metabolome biochemistry, not microbiome composition or gene expression, corresponds to elevated biogeochemical function in the hyporheic zone

Biogeochemical hotspots are pervasive at terrestrial-aquatic interfaces, particularly within groundwater-surface water mixing zones (hyporheic zones), and they are critical to understanding spatiotemporal variation in biogeochemical cycling. Here, we use multi omic comparisons of hotspots to low-activity sediments to gain mechanistic insight into hyporheic zone organic matter processing. We hypothesized that microbiome structure and function, as described by metagenomics and metaproteomics, would distinguish hotspots from low-activity sediments through a shift towards carbohydrate-utilizing metabolic pathways and elucidate discrete mechanisms governing organic matter processing in each location. We also expected these differences to be reflected in the metabolome, whereby hotspot carbon (C) pools and metabolite transformations therein would be enriched in sugar-associated compounds. In contrast to expectations, we found pronounced phenotypic plasticity in the hyporheic zone microbiome that was denoted by similar microbiome structure, functional potential, and expression across sediments with dissimilar metabolic rates. Instead, diverse nitrogenous metabolites and biochemical transformations characterized hotspots. Metabolomes also corresponded more strongly to aerobic metabolism than bulk C content only (explaining 67% vs. 42% of variation), and bulk C did not improve statistical models based on metabolome composition alone. These results point to organic nitrogen as a significant regulatory factor influencing hyporheic zone organic matter processing. Based on our findings, we propose incorporating knowledge of metabolic pathways associated with different chemical fractions of C pools into ecosystem models will enhance prediction accuracy.

molecular biology↗

bioRxiv2026

Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer's and wild-type mice

Lactate, a well-known metabolite and signalling molecule, holds therapeutic potential for neurodegenerative diseases. Here, we investigated the effects of chronic lactate treatment on cognition and molecular biomarkers in the 5XFAD mouse model of Alzheimers disease (AD) and in wild-type (WT) controls using behavioural testing alongside proteomic and transcriptomic analyses. Mice received lactate or vehicle injections 4 days per week for 11 weeks, with behavioural testing before and after the treatment period. Lactate improved working memory in late-treated AD mice, without eliciting anxiety-like behaviour. At the molecular level, lactate reduced Il1b expression, and in a sex-dependent manner, normalised NEFL, and enhanced synaptic integrity proteins (OPCML, PPFIA2, STXBP3, SYT1, VGLUT2, VSNL1) in AD mice, while also augmenting mitochondrial regulators (ATP5G2, GRPEL1, SLC25A23) across genotypes. Notably, lactate upregulated low-abundance ionotropic glutamate receptor mRNAs (Grik3, Grin2c, Grid2ip) in female AD mice, indicating enhanced glutamatergic signalling. In WT mice, lactate increased expression of neurotrophic factors (Bdnf, Igf1, Vegfa), anti-inflammatory cytokines (Il4 and Il13), and the neuronal lactate transporter Mct2, suggesting promoted neuronal resilience. Together, these findings indicate that lactate treatment can mitigate cognitive decline and enhance molecular pathways of resilience in AD, warranting larger, age-stratified studies to validate its therapeutic potential and elucidate underlying mechanisms.

animal behavior and cognition↗