Biology subjects

Ali, M.

Publications and source records attributed to Ali, M..

At least 91 records · Page 5Linked to original sources

bioRxiv2021

Sugar Beet Extract Acts as a Natural Bio-Stimulant for Physio-Biochemical analysis of Hordeum Vulgare L. under Induced Salinity Stress

Change in climate of the entire globe due to elevated temperature and minimum annual rainfall in barren zone frequently leads to salinity of soil. The current study was aimed to evaluate the importance of sugar beet extract (SBE) as a bio-stimulant to improve the adverse damages of induced salinity stress (40mM) on growth, oosmolytes and antioxidant defense system of barley (Hordeum vulgare L.). Pot experiment was carried in green house under different concentrations of SBE (10%, 20%, 30%, 40%, 50%) pre-soaked seeds of Hordeum vulgare for 5 hours SBE was analyzed for glycine betaine (100mmol/kg), betalains (1.3mg/l), phenolics (1.30g/100ml), flavonoids (0.59mg/ml), carotenoids (0.23ml/100ml), vitamin E (0.002%), vitamin C (8.04g/100ml), sugar (8g/100ml), protein (1.39mg/100ml), and oxalic acid (38mg/100ml) while Ca (13.72mg/l), Mg (7.121 mg/l) and K (11.45mg/l) contents were also determined. We found significant improvement in germination parameters of Hordeum vulgare L. via SB extract on coefficient of velocity of emergence (CVE), mean emergence time (MET), germination energy (GE), timson germination index (TGI), germination rate index (GRI) and time to 50% emergence (E50) under induced salinity stress. However, photosynthetic pigments, e.g., chlorophyll and carotenoids were enhanced using 40% SB extract, soluble sugar, protein, proline, POD, MDA with 50% SB extract while SOD and H2O2 in 20% SBE, respectively. Our findings suggested that SB extract promotes both agronomical and physiological attributes, is a positive way to enhance our economy by increasing crop yields in arid and semi-arid areas along with plant tolerance to under induced salinity stress. HighlightsThe recent study is of utmost importance owing to the following reasons:[tpltrtarr] Changes in climatic condition results in salinity, droughts, floods, earthquakes, fluctuation in temperature and other environmental hazards. [tpltrtarr]Salinity stress has myriad of damaging effects on crop growth and productivity and becoming a global issue of major concern especially in the Asian countries including Pakistan. Statistical analysis showed that 6.30 million of lands is affected with salinity. [tpltrtarr]Barley (Hordeum Vulgare L.) being an important crop of economic and nutritional value has been facing salinity stress condition in Pakistan, resulting in productivity reduction and ultimately paving the way for food scarcity and crippling economy. [tpltrtarr]The sole purpose of this research article is to assess and ameliorate the physio-biochemical responses via application of sugar beet extract as bio-stimulants in Barley (Hordeum Vulgare L.) grown under induced salinity stress; in order to cope with the dire consequences of salinity stress especially in the southern areas of Pakistan being badly affected by salt stress. [tpltrtarr]Furthermore, there is a great need for adaptive measures suggested by the present research and other findings made by researchers in pursuit of tackling this alarming global menace.

plant biology↗

bioRxiv2021

Maturation of Human Long-lived Plasma Cells Results in Resistance to Apoptosis by Transcriptional and Epigenetic Regulation

Antibody secreting cells (ASC) circulate after vaccination and migrate to the bone marrow (BM) where a subset known as long-lived plasma cells (LLPC) persist and secrete antibodies for a lifetime. The mechanisms of how circulating ASC become LLPC are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared to BM LLPC. LLPC acquire transcriptional and epigenetic changes in the apoptosis pathway to support their survival. Upregulation of pro-survival gene expression accompanies downregulation of pro-apoptotic gene expression in LLPC. While pro-apoptotic gene loci are less accessible, pro-survival gene loci are not always accompanied by accessibility changes. Importantly, we show similar LLPC morphological and transcriptional maturation of blood ASC in response to the novel in vitro BM mimetic. In all, our study demonstrates that blood ASC in the BM microniche must undergo morphological and molecular changes to mature into apoptotic-resistant LLPC.

immunology↗

bioRxiv2021

Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities

Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, current methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a scalable viral peptide discovery approach covering 229 RNA viruses that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an {Phi}xFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its {Phi}xFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction blocks SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.

biochemistry↗

bioRxiv2021

Proteome-scale amino-acid resolution footprinting of protein-binding sites in the intrinsically disordered regions of the human proteome

Specific protein-protein interactions are central to all processes that underlie cell physiology. Numerous studies using a wide range of experimental approaches have identified tens of thousands of human protein-protein interactions. However, many interactions remain to be discovered, and low affinity, conditional and cell type-specific interactions are likely to be disproportionately under-represented. Moreover, for most known protein-protein interactions the binding regions remain uncharacterized. We previously developed proteomic peptide phage display (ProP-PD), a method for simultaneous proteome-scale identification of short linear motif (SLiM)-mediated interactions and footprinting of the binding region with amino acid resolution. Here, we describe the second-generation human disorderome (HD2), an optimized ProP-PD library that tiles all disordered regions of the human proteome and allows the screening of ~1,000,000 overlapping peptides in a single binding assay. We define guidelines for how to process, filter and rank the results and provide PepTools, a toolkit for annotation and analysis of identified hits. We uncovered 2,161 interaction pairs for 35 known SLiM-binding domains and confirmed a subset of 38 interactions by biophysical or cell-based assays. Finally, we show how the amino acid resolution binding site information can be used to pinpoint functionally important disease mutations and phosphorylation events in intrinsically disordered regions of the human proteome. The HD2 ProP-PD library paired with PepTools represents a powerful pipeline for unbiased proteome-wide discovery of SLiM-based interactions.

biochemistry↗

bioRxiv2021

Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya

Understanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control. In a 3 year case-control study, we investigated typhoid among children aged <16 years (4,670 febrile cases and 8,549 age matched controls) living in an informal settlement, Nairobi, Kenya. 148 S. Typhi isolates from cases and 95 from controls (stool culture) were identified; a carriage frequency of 1%. Whole-genome sequencing showed 97% of cases and 88% of controls were genotype 4.3.1 (Haplotype58), with the majority of each (76% and 88%) being multidrug-resistant strains in 3 sublineages of H58 genotype (East Africa 1 (EA1), EA2, and EA3), with sequences from cases and carriers intermingled. The high rate of multidrug-resistant H58 S. Typhi, and the close phylogenetic relationships between carriers and controls, provides evidence for the role of carriers as a reservoir for the community spread of typhoid in this setting.

physiology↗

bioRxiv2021

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimers disease mouse model

Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow (CBF) and exacerbates short-term memory loss in multiple mouse models of Alzheimers disease (AD). Here, we report that Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood brain barrier (BBB) hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall eNOS protein concentrations, increased occludin levels, and decreased the penetration of circulating Evans Blue dye across the BBB into the brain parenchyma, suggesting increased BBB integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signaling in APP/PS1 mice contributes to aberrant eNOS/occludin- associated BBB permeability, increases the incidence of capillary stalls, and leads to reductions in CBF. Reducing leucocyte adhesion by inhibiting luminal VEGF signaling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in AD patients.

neuroscience↗

bioRxiv2021

Effect of exogenously applied alpha-tocopherol on vital agronomic, physiological and biochemical attributes of Lentil (Lens culinaris Medik.) under induced drought stress

Water being a vital part of cell protoplasm plays a significant role in sustaining life on earth; drastic changes in climatic condition leads to limit the availability of water and causing other environmental chaos. Alpha-tocopherol being a powerful antioxidant plays a vital role in scavenging the ill effects of oxidative stress. A pot experiment was conducted by exposing lentil cultivar (Punjab-2009) to varying levels of induced drought stress, sprinkled with -tocopherol 100, 200 and 300 mg/L. Induced water deficit stress conditions caused a pronounced decline in growth parameters including absolute growth rate (AGR), leaf area index (LAI), leaf area ratio (LAR), root shoot ratio (RSR), relative growth rate (RGR), chlorophyll a, b, total chlorophyll content, carotenoids and soluble protein content (SPC) which were significantly enhanced by exogenously applied -tocopherol. Moreover, a significant increase was reported in total proline content (TPC), soluble sugar content (SSC), glycine betaine (GB) content, endogenous tocopherol levels, ascorbate peroxidase (APX), catalase (CAT) peroxidase (POD) and superoxide dismutase (SOD) activities. On contrary, exogenously applied -tocopherol significantly reduced the concentrations of malondialdehyde (MDA) and hydrogen peroxide (H2O2). In conclusion, it was confirmed that exogenously applied -tocopherol under induced drought stress regimes ameliorated drought stress tolerance potential of lentil cultivar to a great extent; by enhancing growth, physiological and biochemical attributes.

plant biology↗

bioRxiv2020

Feeding Experimentation Device version 3 (FED3): An open-source home-cage compatible device for measuring food intake and operant behavior

Feeding is critical for survival and disruption in the mechanisms that govern food intake underlie disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation: The Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of feeding behavior with minimal experimenter intervention. It has a programmable output for synchronizing behavior with optogenetic stimulation or neural recordings. Finally, FED3 design files are open-source and freely available, allowing researchers to modify FED3 to suit their needs. In this paper we demonstrate the utility of FED3 in a range of experimental paradigms. In BriefUsing a novel, high-throughput home cage feeding platform, FED3, Matikainen-Ankney et al. quantify food intake and operant learning in groups of mice conducted at multiple institutions across the globe. Results include rates of operant efficiency, circadian feeding patterns, and operant optogenetic self-stimulation. Highlights O_LIThe Feeding Experimentation Device version 3(FED3) records food intake and operant behavior in rodent home cages. C_LIO_LIAnalysis of food intake includes total intake, meal pattern analysis, and circadian analysis of feeding patterns. C_LIO_LIFED3 also allows for operant behavioral assays to examine food learning and motivation. C_LI

animal behavior and cognition↗

bioRxiv2020

Defining binding motifs and dynamics of the multi-pocket FERM domain from ezrin, radixin, moesin and merlin

The ERM (ezrin, radixin and moesin) family of proteins and the related protein merlin participate in signaling events at the cell cortex. The proteins share an N-terminal FERM (band Four-point-one (4.1) ERM) domain comprised of three subdomains (F1, F2, and F3) that hold multiple binding sites for short linear peptide motifs. By screening the FERM domains of the ERMs and merlin against a phage library that display peptides representing the intrinsically disordered regions of the human proteome we identified more than 220 FERM binding peptides. The majority of the peptides contained an apparent Yx[FILV] motif, but ligands with alternative motifs were also found. Interactions with thirteen peptides were validated using a fluorescence polarization assay, and interactions with seven full-length proteins were validated through pull-down experiments. We investigated the energy landscapes of interactions between the moesin FERM domain and representative set of ligands using Rosetta FlexPepDock computational peptide docking protocols, which provide a detailed molecular understanding of the binding of peptides with distinct motifs (YxV and E[Y/F]xDFYDF) to different sites on the F3 subdomain. A third motif (FY[D/E]L(4-5x)PLxxx[L/V]) was proposed to bind more diffusely. By combining competition and modeling experiments, we further uncovered interdependencies between different types of ligands. The study expands the motif-based interactomes of the ERMs and merlin, and suggests that the FERM domain acts as a switchable interaction hub where one class of ligands to the F3 subdomain allosterically regulates binding of other F3 ligands.

biochemistry↗

bioRxiv2020

Cytoplasmic short linear motifs in ACE2 and integrin beta3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

The spike protein of the SARS-CoV-2 interacts with angiotensin converting enzyme 2 (ACE2) and enters the host cell by receptor-mediated endocytosis. Concomitantly, evidence is pointing to the involvement of additional host cell receptors, such as integrins. The cytoplasmic tails of ACE2 and integrin {beta}3 contain a plethora of predicted binding motifs. Here, we confirm the functionality of some of these motifs through affinity measurements. The class I PDZ binding motif in the ACE2 cytoplasmic tail binds the first PDZ domain of the scaffold protein NHERF3. The clathrin-adaptor subunit AP2 2 interacts with an endocytic motif in the ACE2 with low affinity and the interaction is abolished by phosphorylation of Tyr781. Furthermore, the C-terminal region of integrin b3 contains a LC3-interacting region, and its interaction with ATG8 domains is enhanced by phosphorylation. Together, our data provides possible molecular links between host cell receptors and endocytosis and autophagy. One sentence summaryAffinity measurements confirmed binding of short linear motifs in the cytoplasmic tails of ACE2 and integrin {beta}3, thereby linking the receptors to endocytosis and autophagy.

biochemistry↗

bioRxiv2020

Comparative transcriptomics identifies differences in the regulation of the floral transition between Arabidopsis and Brassica rapa cultivars

The timing of the floral transition affects reproduction and yield, however its regulation in crops remains poorly understood. Here, we use RNA-Seq to determine and compare gene expression dynamics through the floral transition in the model species Arabidopsis thaliana and the closely related crop Brassica rapa. A direct comparison of gene expression over time between species shows little similarity, which could lead to the inference that different gene regulatory networks are at play. However, these differences can be largely resolved by synchronisation, through curve registration, of gene expression profiles. We find that different registration functions are required for different genes, indicating that there is no common developmental time to which Arabidopsis and B. rapa can be mapped through gene expression. Instead, the expression patterns of different genes progress at different rates. We find that co-regulated genes show similar changes in synchronisation between species, suggesting that similar gene regulatory sub-network structures may be active with different wiring between them. A detailed comparison of the regulation of the floral transition between Arabidopsis and B. rapa, and between two B. rapa accessions reveals different modes of regulation of the key floral integrator SOC1, and that the floral transition in the B. rapa accessions is triggered by different pathways, even when grown under the same environmental conditions. Our study adds to the mechanistic understanding of the regulatory network of flowering time in rapid cycling B. rapa under long days and highlights the importance of registration methods for the comparison of developmental gene expression data.

plant biology↗

bioRxiv2020

CLEP: A Hybrid Data- and Knowledge- Driven Framework for Generating Patient Representations

As machine learning and artificial intelligence become more useful in the interpretation of biomedical data, their utility depends on the data used to train them. Due to the complexity and high dimensionality of biomedical data, there is a need for approaches that combine prior knowledge around known biological interactions with patient data. Here, we present CLEP, a novel approach that generates new patient representations by leveraging both prior knowledge and patient-level data. First, given a patient-level dataset and a knowledge graph containing relations across features that can be mapped to the dataset, CLEP incorporates patients into the knowledge graph as new nodes connected to their most characteristic features. Next, CLEP employs knowledge graph embedding models to generate new patient representations that can ultimately be used for a variety of downstream tasks, ranging from clustering to classification. We demonstrate how using new patient representations generated by CLEP significantly improves performance in classifying between patients and healthy controls for a variety of machine learning models, as compared to the use of the original transcriptomics data. Furthermore, we also show how incorporating patients into a knowledge graph can foster the interpretation and identification of biological features characteristic of a specific disease or patient subgroup. Finally, we released CLEP as an open source Python package together with examples and documentation.

bioinformatics↗

bioRxiv2020

Localized Proteotoxic Stress in Mitochondrial Intermembrane Space and Matrix Elicits Sub-compartment Specific Response Pathways Governed by Unique Modulators

The double-membrane-bound architecture of mitochondria, essential for ATP production, sub-divides the organelle into inter-membrane space (IMS) and matrix. IMS and matrix possess contrasting oxido-reductive environments and distinct protein quality control (PQC) machineries resulting different protein folding environments. To understand the nature of stress response elicited by equivalent proteotoxic stress to sub-mitochondrial compartments, we fused well-described bipartite or matrix-targeting signal sequences to misfolding and aggregation-prone stressor proteins to target and impart stress to yeast mitochondrial IMS or matrix. We show, mitochondrial proteotoxicity leads to growth arrest of yeast cells of varying degrees depending on nature of stressor proteins and the intra-mitochondrial location of stress. Next, using transcriptomics and proteomics, we report a comprehensive stress response elicited by two types of targeting signal-fused stressor proteins. Among global responses by mitochondria-targeted stressors by both types of signal sequences, an adaptive response of abrogated mitochondrial respiration and concomitant upregulation of glycolysis is uncovered. Beyond shared stress responses, specific signatures due to stress within mitochondrial sub-compartments are also revealed. We report that bipartite signal sequence-fused stressor proteins eliciting stress to IMS, leads to specific upregulation of IMS-chaperones and TOM complex components. In contrast, matrix-targeted stressors lead to specific upregulation of matrix-chaperones and cytosolic PQC components. Finally, by systematic genetic interaction using deletion strains of differentially upregulated genes, we found prominent modulatory role of TOM complex components during IMS-stress response. In contrast, VMS1 markedly modulates the stress response originated from matrix.

cell biology↗

bioRxiv2020

Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis

Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed anti-fibrotic effects in an animal model of scleroderma and in patient-derived diffuse cutaneous (dc)SSc fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium signaling. The anti-fibrotic effect of BRD4 inhibition was at least in part mediated by downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII-) and reduction of intracellular calcium concentrations. These results suggest that targeting calcium pathways or BRD4 might be novel therapeutic approaches for progressive tissue fibrosis.

pharmacology and toxicology↗

bioRxiv2020

GroEL/ES Buffers Entropic Traps In Folding Pathway During Evolution Of A Model Substrate

The folding landscape of proteins can change during evolution with the accumulation of mutations that may introduce entropic or enthalpic barriers in the protein folding pathway, making it a possible substrate of molecular chaperones in vivo. Can the nature of such physical barriers of folding dictate the feasibility of chaperone-assistance? To address this, we have simulated the evolutionary step to chaperone-dependence keeping GroEL/ES as the target chaperone and GFP as a model protein in an unbiased screen. We find that the mutation conferring GroEL/ES dependence in vivo and in vitro encode an entropic trap in the folding pathway rescued by the chaperonin. Additionally, GroEL/ES can edit the formation of non-native contacts similar to DnaK/J/E machinery. However, this capability is not utilized by the substrates in vivo. As a consequence, GroEL/ES caters to buffer mutations that predominantly cause entropic traps, despite possessing the capacity to edit both enthalpic and entropic traps in the folding pathway of the substrate protein.

molecular biology↗

bioRxiv2020

Computational vaccinology based development of multi-epitope subunit vaccine for protection against the Norovirus infections

Human Norovirus belong to family Calciviridae, it was identified in the outbreak of gastroenteritis in Norwalk, due to its seasonal prevalence known as "winter vomiting disease". Treatment of Norovirus infection is still mysterious because there is no effective antiviral drugs or vaccine developed to protect against the infection, to eradicate the infection an effective vaccine should be developed. In this study capsid protein (A7YK10), small protein (A7YK11) and polyprotein (A7YK09) were utilized. These proteins were subjected to B and T cell epitopes prediction by using reliable immunoinformatics tools. The antigenic and non-allergenic epitopes were selected for subunit vaccine, which can activate cellular and humoral immune responses. Linkers joined these epitopes together. The vaccine structure was modelled and validated by using Errat, ProSA and rampage servers. The modelled vaccine was docked with TLR-7. Stability of the docked complex was evaluated by MD simulation. In order to apply the concept in a wet lab, the reverse translated vaccine sequence was cloned in pET28a (+). The vaccine developed in this study requires experimental validation to ensure its effectiveness against the disease.

immunology↗

bioRxiv2020

Electroactive biofilms on surface functionalized anodes: the anode respiring behavior of a novel electroactive bacterium, Desulfuromonas acetexigens

Surface chemistry is known to influence the formation, composition and electroactivity of electron-conducting biofilms with however limited information on the variation of microbial composition and electrochemical response during biofilm development to date. Here we present voltammetric, microscopic and microbial community analysis of biofilms formed under fixed applied potential for modified graphite electrodes during early (90 h) and mature (340 h) growth phases. Electrodes modified to introduce hydrophilic groups (-NH2, -COOH and -OH) enhance early-stage biofilm formation compared to unmodified or electrodes modified with hydrophobic groups (-C2H5). In addition, early-stage films formed on hydrophilic electrodes were dominated by the gram-negative sulfur-reducing bacterium Desulfuromonas acetexigens while Geobacter sp. dominated on -C2H5 and unmodified electrodes. As biofilms mature, current generation becomes similar, and D. acetexigens dominates in all biofilms irrespective of surface chemistry. Electrochemistry of pure culture D. acetexigens biofilms reveal that this microbe is capable of forming electroactive biofilms producing considerable current density of > 9 A/m2 in a short period of potential induced growth (~19 h followed by inoculation) using acetate as an electron donor. The inability of D. acetexigens biofilms to use H2 as a sole source electron donor for current generation shows promise for maximizing H2 recovery in single-chambered microbial electrolysis cell systems treating wastewaters. HighlightsO_LIAnode surface chemistry affects the early stage biofilm formation. C_LIO_LIHydrophilic anode surfaces promote rapid start-up of current generation. C_LIO_LICertain functionalized anode surfaces enriched the Desulfuromonas acetexigens. C_LIO_LID. acetexigens is a novel electroactive bacteria. C_LIO_LID. acetexigens biofilms can produce high current density in a short period of potential induced growth C_LIO_LID. acetexigens has the ability to maximize the H2 recovery in MEC. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/974261v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@1a9c7a5org.highwire.dtl.DTLVardef@1722697org.highwire.dtl.DTLVardef@143b996org.highwire.dtl.DTLVardef@14d4a60_HPS_FORMAT_FIGEXP M_FIG TOC - Graphical abstract C_FIG

bioengineering↗

bioRxiv2020

Voluntary running does not increase capillary blood flow but promotes neurogenesis and short-term memory in the APP/PS1 mouse model of Alzheimers disease

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer s disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer s patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer s disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we examined the impact of three months of voluntary wheel running in [~]1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and cerebral blood flow. Our findings that exercise led to improved memory function, a trend toward reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and no changes in amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer s related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall cortical blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer s disease. Overall, our results replicate previous findings that exercise is able to ameliorate certain aspects of Alzheimer s disease pathology, but show that this benefit does not appear to act through increases in cerebral blood flow.

neuroscience↗