Biology subjects

Ahmed, Z.

Publications and source records attributed to Ahmed, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Discovering biomarkers associated and predicting cardiovascular disease with high accuracy using a novel nexus of machine learning techniques for precision medicine

Personalized interventions are deemed vital given the intricate characteristics, advancement, inherent genetic composition, and diversity of cardiovascular diseases (CVDs). The appropriate utilization of artificial intelligence (AI) and machine learning (ML) methodologies can yield novel understandings of CVDs, enabling improved personalized treatments through predictive analysis and deep phenotyping. In this study, we proposed and employed a novel approach combining traditional statistics and a nexus of cutting-edge AI/ML techniques to identify significant biomarkers for our predictive engine by analyzing the complete transcriptome of CVD patients. After robust gene expression data pre-processing, we utilized three statistical tests (Pearson correlation, Chi-square test, and ANOVA) to assess the differences in transcriptomic expression and clinical characteristics between healthy individuals and CVD patients. Next, the Recursive Feature Elimination (RFE) classifier assigned rankings to transcriptomic features based on their relation to the case-control variable. The top ten percent of commonly observed significant biomarkers were evaluated using four unique ML classifiers (Random Forest, Support Vector Machine, Xtreme Gradient Boosting Decision Trees, and k-Nearest Neighbors). After optimizing hyperparameters, the ensembled models, which were implemented using a soft voting classifier, accurately differentiated between patients and healthy individuals. We have uncovered 18 transcriptomic biomarkers that are highly significant in the CVD population that were used to predict disease with up to 96% accuracy. Additionally, we cross-validated our results with clinical records collected from patients in our cohort. The identified biomarkers served as potential indicators for early detection of CVDs. With its successful implementation, our newly developed predictive engine provides a valuable framework for identifying patients with CVDs based on their biomarker profiles.

genomics↗

bioRxiv2023

Glymphatic Inhibition Exacerbates Tau Propagation in an Alzheimers Disease Model

BackgroundThe aggregation and spread of misfolded amyloid structured proteins, such as tau and -synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimers and Parkinsons disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins. MethodsIn this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brain in vivo prior to brain extraction for immunohistochemical characterisation. ResultsOur findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus and cortex following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the aforementioned alterations were attenuated. ConclusionsThese results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.

neuroscience↗

bioRxiv2023

Increasing chemotherapeutic efficacy using doxorubicin and sodium bicarbonate releasing injectable chitosan-polyethylene glycol hydrogels

Modulation of pH is crucial to maintaining the chemical homeostasis of biological environments. The irregular metabolic pathways exhibited by cancer cells result in the production of acidic byproducts that are excreted and accumulate in the extracellular tumor microenvironment, reducing its pH. As a consequence of the lower pH in tumors, cancer cells increase the expression of metastatic phenotypes and chemotherapeutic resistance. A significant limitation in current cancer therapies is the inability to locally deliver the chemotherapy, leading to significant damage to healthy cells in systemic administration. To overcome these challenges, we present an injectable chitosan-polyethylene glycol hydrogel that is dual-loaded with doxorubicin and sodium bicarbonate providing alkaline buffering of extracellular acidity and simultaneous chemotherapeutic delivery to increase chemotherapeutic efficacy. We conducted in vitro studies of weak base chemotherapeutic and alkaline buffer release from the hydrogel. The release of doxorubicin from hydrogels increased in a low pH environment and was dependent on the encapsulated sodium bicarbonate concentration. We investigated the influence of pH on doxorubicin efficacy and viability of MCF-7 and MDA-MB-231 breast cancer cell lines. The results show a 2 to 3 fold increase in IC50 values from neutral pH to low pH, showing decreased cancer cell viability at neutral pH as compared to acidic pH. The IC50 results were shown to correlate with a decrease in intracellular uptake of doxorubicin at low pH. The proposed hydrogels were confirmed to be non-toxic to healthy MCF-10A mammary epithelial cells. Rheological studies were performed to verify that the dual loaded hydrogels were injectable. The mechanical and release properties of the hydrogels were maintained after extended storage. The chemotherapeutic activity of doxorubicin was evaluated in the presence of the proposed pH regulating hydrogels. The findings suggest a promising non-toxic, biodegradable hydrogel buffer delivery system that can achieve two simultaneous important goals of local acidosis neutralization and chemotherapeutic release.

bioengineering↗

bioRxiv2023

Investigating variant and expression of CVD genes associated phenotypes among high-risk Heart Failure patients

Cardiovascular disease (CVD) is a leading cause of premature mortality in the US and the world. CVD comprises of several complex and mostly heritable conditions, which range from myocardial infarction to congenital heart disease. Here, we report our findings from an integrative analysis of gene expression, disease-causing gene variants, and associated phenotypes among CVD populations, with a focus on high-risk Heart Failure (HF) patients. We built a cohort using electronic health records (EHR) of consented patients with available samples, and then performed high-throughput whole-genome and RNA sequencing (RNA-seq) of key genes responsible for HF and other CVD pathologies. We also incorporated a translational aspect to our study by integrating genomics findings with patient medical records. This involved linking ICD-10 codes with our gene expression and variant data to identify associations with HF and other CVDs. Our in-depth gene expression analysis revealed differentially expressed genes associated with HF (41 genes) and other CVDs (23 genes). Furthermore, a variant analysis of whole-genome sequence data of CVD patients identified genes with altered gene expression (FLNA, CST3, LGALS3, and HBA1) with functional and nonfunctional mutations in these genes. Our study highlights the importance of an integrative approach that leverages gene expression, genetic mutations, and clinical data that will allow the prioritization of key driver genes for complex diseases to improve personalized healthcare.

genomics↗

bioRxiv2023

Integrated ACMG approved genes and ICD codes for the translational research and precision medicine

Timely understanding of biological secrets of complex diseases will ultimately benefit millions of individuals by reducing the high risks for mortality and improving the quality of life with personalized diagnoses and treatments. Due to the advancements in sequencing technologies and reduced cost, genomics data is developing at an unmatched pace and levels to foster translational research and precision medicine. Over ten million genomics datasets have been produced and publicly shared in the year 2022. Diverse and high-volume genomics and clinical data have the potential to broaden the scope of biological discoveries and insights by extracting, analyzing, and interpreting the hidden information. However, the current and still unresolved challenges include the integration of genomic profiles of the patients with their medical records. The disease definition in genomics medicine is simplified, when in the clinical world, diseases are classified, identified, and adopted with their International Classification of Diseases (ICD) codes, which are maintained by the World Health Organization (WHO). Several biological databases have been produced, which includes information about human genes and related diseases. However, still, there is no database exists, which can precisely link clinical codes with relevant genes and variants to support genomic and clinical data integration for clinical and translation medicine. In this project, we are focused on the development of an annotated gene-disease-code database, which is accessible through an online, cross-platform, and user-friendly application i.e., PAS-GDC. However, our scope is limited to the integration of ICD-9 and ICD-10 codes with the list of genes approved by the American College of Medical Genetics and Genomics (ACMG). Results include over seventeen thousand diseases and four thousand ICD codes, and over eleven thousand gene-disease-code combinations.

bioinformatics↗

bioRxiv2022

Evaluation of Association between CSN2 Genetic Marker 7:32016718C>A with A1/A2 Milk in Pakistani Buffaloes

Milk is an essential part of the diet that plays an important role in human growth and development due to the presence of different components like calcium, fats and proteins. Among six major proteins of the milk, {beta}-casein is one of them which is being investigated here due to the A1/A2 milk genetic variants and its associated gene of CSN2 in one of the valued species of Bubalus bubalis in Pakistan. Fifty buffalo samples were genotyped using the ARMS-PCR technique. CSN2 gene locus 32016718C>A is located on Chr.7 with CDS position c.350C>A on its 7th exon as per (GenBank transcript ID: XM_006071124.3). In {beta}-casein, 117th amino acid position where histidine (CAT) is responsible for A1 and proline (CCT) for A2 milk phenotype. A2 milk is considered to be healthy for human health due to the absence of bioactive peptide {beta}-casomorphin-7 (BCM7) in comparison with A1 milk. The current results showed that overall, 100% buffalo population is homozygous wild-type (CC) which means no mutant allele is detected in all studied samples therefore, Pakistani buffalo is exclusively producing A2 milk. Furthermore, this work may also be conducted on different buffalo breeds in Pakistan as well as other species of cattle, goat, sheep and camel to explore their genomic architecture for this valued trait.

genetics↗

bioRxiv2022

Genetic Association of CSN2 Variant 6:85451298C>A with A1/A2 Milk Phenotype in Pakistani Cows

The cow is a very important mammal from the bovine family renowned for providing milk, meat and hide around the globe. {beta}-casein is one of the principal proteins found in cows milk encoded by the CSN2 gene with 12-13 reported genetic variants present on Chr.6 in the cows genome. The current study investigated A1/A2 associated variant g.6:85451298C>A (rs43703011) in exon 7th according to the GenBank ID: M55158.1 position 8101C>A (c.245C>A), which is responsible to change the 67th amino acid of the {beta}-casein polypeptide from proline (CCT, A2) to histidine (CAT, A1). The milk containing A2 protein variant is good while A1 milk has some negative effects on human health due to the production of {beta}-casmomorphin-7. Genetic screening of the subject variant was conducted using ARMS-PCR on 48 native and exotic cows from Pakistan. Our initial results showed that 37.5% of the population is homozygous wild-type (C/C), 56.25% is heterozygous (C/A) and the remaining 6.25% is homozygous mutant-type (A/A). Additionally, the Chi-square association test was applied using the PLINK data analysis toolset which presented a significant p-value of 2.811x10-3 and OR of 3.8 with an alternative allele frequency of 0.2 and 0.5 in native and exotic populations respectively. Hence, there is significant variability in A1/A2 genotype which may be addressed by adopting selective breeding programs in Pakistan.

genetics↗

bioRxiv2022

Universal guide for skull extraction and custom-fitting of implants to continuous and discontinuous skulls

Intracranial neurophysiological recordings require chronic implants to provide transcranial access to the brain. Especially in larger animals, which participate in experiments over extended periods of time, implants should match the skull curvature to promote osseointegration and avoid tissue and bacterial ingress over time. Proposed CAD methods for designing implants to date have focused on naive animals with continuous and even skull surfaces and calculate Boolean differences between implant and skull surface to fit the implant to the skull curvature. However, custom-fitting by calculating the difference fails, if a discontinuous skull surface needs to be matched. Also, the difference method does not allow designs with constant material thickness along the skull curvature, e.g. to allow fixed screw lengths. We present a universal step-by-step guide for custom-fitting implants which overcomes these limitations. It is suited for unusual skull conditions, like surface discontinuities or irregularities and includes virtual bending as a process to match skull surfaces while maintaining implant thickness. We demonstrate its applicability for a wide spectrum of scenarios, ranging from complex-shaped single-pieced implants to detailed multi-component implant systems built on even or discontinuous skull. The guide uses only a few software tools and the final virtual product can be manufactured using CNC milling or 3D printing. A detailed description of this process is available on GitHub including step-by-step video instructions suitable for users without any prior knowledge in CAD programming. We report the experience with these implants over several years in 11 rhesus monkeys. Significance StatementChronic implants are essential for intracranial neurophysiological recordings. In this study we show how to custom-design and -fit such implants for rhesus monkeys (Macacca mulatta). Different to existing approaches, our procedure is not limited to even skull surfaces but can be applied to discontinuous or irregular surfaces. It furthermore presents a description of virtual implant bending to match the skull curvature while maintaining implant thickness. The final virtual product can be manufactured using CNC milling or 3D printing. In contrast to previous studies, this guide is suited for users without any prior expertise in CAD programming using our step-by-step video instructions.

neuroscience↗

bioRxiv2021

Overexpression of Reticulon 3 enhances CNS axon regeneration and functional recovery after injury

CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-66. Here, we focused on RTN3 as its contribution in CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury.

neuroscience↗

bioRxiv2021

Phosphorylation of the M1 muscarinic acetylcholine receptor mediates protection in neurodegenerative disease

There are currently no treatments that can slow the progression of neurodegenerative diseases such as Alzheimers disease (AD). There is, however, a growing body of evidence that activation of the M1 muscarinic acetylcholine receptor (M1-receptor) can not only restore memory loss in AD patients, but in preclinical animal models can also slow neurodegenerative disease progression. The generation of an effective medicine targeting the M1-receptor has however been severely hampered by associated cholinergic adverse responses. By using genetically engineered mouse models that express a G protein-biased M1-receptor, we recently established that M1-receptor mediated adverse responses can be minimised by ensuring activating ligands maintain receptor phosphorylation/arrestin-dependent signalling. Here, we use these same genetic models in concert with murine prion disease, a terminal neurodegenerative disease showing key hallmarks of AD, to establish that phosphorylation/arrestin-dependent signalling delivers neuroprotection that both extends normal animal behaviour and prolongs the life span of prion diseased mice. Our data point to an important neuroprotective property inherent to the M1-receptor and indicate that next generation M1-receptor ligands designed to drive receptor phosphorylation/arrestin-dependent signalling would potentially show low adverse responses whilst delivering neuroprotection that will slow disease progression.

pharmacology and toxicology↗

bioRxiv2020

Full-length transcript sequencing of human and mouse identifies widespread isoform diversity and alternative splicing in the cerebral cortex

Alternative splicing is a post-transcriptional regulatory mechanism producing multiple distinct mRNA molecules from a single pre-mRNA. Alternative splicing has a prominent role in the central nervous system, impacting neurodevelopment and various neuronal functions as well as being increasingly implicated in brain disorders including autism, schizophrenia and Alzheimers disease. Standard short-read RNA-Seq approaches only sequence fragments of the mRNA molecule, making it difficult to accurately characterize the true nature of RNA isoform diversity. In this study, we used long-read isoform sequencing (Iso-Seq) to generate full-length cDNA sequences and map transcript diversity in the human and mouse cerebral cortex. We identify widespread RNA isoform diversity amongst expressed genes in the cortex, including many novel transcripts not present in existing genome annotations. Alternative splicing events were found to make a major contribution to RNA isoform diversity in the cortex, with intron retention being a relatively common event associated with nonsense-mediated decay and reduced transcript expression. Of note, we found evidence for transcription from novel (unannotated genes) and fusion events between neighbouring genes. Although global patterns of RNA isoform diversity were found to be generally similar between human and mouse cortex, we identified some notable exceptions. We also identified striking developmental changes in transcript diversity, with differential transcript usage between human adult and fetal cerebral cortex. Finally, we found evidence for extensive isoform diversity in genes associated with autism, schizophrenia and Alzheimers disease. Our data confirm the importance of alternative splicing in the cerebral cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain. We provide this transcript level data as a resource to the scientific community.

genomics↗

bioRxiv2020

Novel Loss-of-Function Mutations in COCH Cause Autosomal Recessive Nonsyndromic Deafness

COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly deafness in mice and humans. Two forms of deafness are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used mini-gene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA-splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA-splicing, and highlights the need to investigate the effect of coding variants on RNA-splicing.

genetics↗

bioRxiv2020

Differential aberrant structural synaptic plasticity in axons and dendrites ahead of their degeneration in tauopathy

Neurodegeneration driven by aberrant tau is a key feature of many dementias. Pathological stages of tauopathy are characterised by reduced synapse density and altered synapse function. Furthermore, changes in synaptic plasticity have been documented in the early stages of tauopathy suggesting that they may be a driver of later pathology. However, it remains unclear if synapse plasticity is specifically linked to the degeneration of neurons. This is partly because, in progressive dementias, pathology can vary widely from cell-to-cell along the prolonged disease time-course. To overcome this variability, we have taken a longitudinal experimental approach to track individual neurons through the progression of neurodegenerative tauopathy. Using repeated in vivo 2-photon imaging in rTg4510 transgenic mice, we have measured structural plasticity of presynaptic terminaux boutons and postsynaptic spines on individual axons and dendrites over long periods of time. By following individual neurons, we have measured synapse density across the neuronal population and tracked changes in synapse turnover in each neuron. We found that tauopathy drives a reduction in density of both presynaptic and postsynaptic structures and that this is partially driven by degeneration of individual axons and dendrites that are spread widely across the disease time-course. Both synaptic loss and neuronal degeneration was ameliorated by reduction in expression of the aberrant P301L transgene, but only if that reduction was initiated early in disease progression. Notably, neurite degeneration was preceded by alterations in synapse turnover that contrasted in axons and dendrites. In dendrites destined to die, there was a dramatic loss of spines in the week immediately before degeneration. In contrast, axonal degeneration was preceded by a progressive attenuation of presynaptic turnover that started many weeks before axon disappearance. Therefore, changes in synapse plasticity are harbingers of degeneration of individual neurites that occur at differing stages of tau-driven neurodegenerative disease, suggesting a cell or neurite autonomous process. Furthermore, the links between synapse plasticity and degeneration are distinct in axonal and dendritic compartments. Key findingsO_LITauopathy driven by tau P301L in rTg4510 mice causes a progressive decrease in density of presynaptic terminaux boutons and postsynaptic dendritic spines in cortical excitatory neurons. C_LIO_LILongitudinal imaging of individual axons and dendrites shows that there is a huge diversity of effects at varying times in different cells. C_LIO_LIDecreases in overall synapse density are driven partly, but not exclusively, by degeneration of dendrites and axons that are distributed widely across the time-course of disease. C_LIO_LISuppression of pathological P301L tau expression can ameliorate accumulation of tau pathology, synapse loss and neurodegeneration, but only if administered early in disease progression. C_LIO_LINeurite degeneration is preceded by aberrant structural synaptic plasticity in a cell-specific way that is markedly different in dendrites and axons. C_LIO_LIDegeneration of dendrites is immediately preceded by dramatic loss of dendritic spines. C_LIO_LIAxonal loss is characterised by a progressive attenuation of presynaptic bouton plasticity that starts months before degeneration. C_LI

neuroscience↗

bioRxiv2019

Grb2 binding induces phosphorylation-independent activation of Shp2

The regulation of phosphatase activity is fundamental to the control of intracellular signalling and in particular the tyrosine kinase-mediated mitogen-activated protein kinase (MAPK) pathway. Shp2 is a ubiquitously expressed protein tyrosine phosphatase and its kinase-induced hyperactivity is associated with many cancer types. In non-stimulated cells we find that binding of the adaptor protein, Grb2, in its monomeric state initiates Shp2 activity independent of phosphatase phosphorylation. Grb2 forms a bidentate interaction with both the N-terminal SH2 and the catalytic domains of Shp2, releasing the phosphatase from its auto-inhibited conformation. Grb2 typically exists as a dimer in the cytoplasm. However, its monomeric state prevails under basal conditions when it is expressed at low concentration, or when it is constitutively phosphorylated on a specific tyrosine residue (Y160). Thus, Grb2 can activate Shp2 and downstream signal transduction, in the absence of extracellular growth factor stimulation or kinase-activating mutations, in response to defined cellular conditions. We identify a polypeptide biotool capable of blocking the Grb2-Shp2 interaction. This peptide down-regulates Shp2 activity in vitro and MAPK signalling in a cancer cell line.

cancer biology↗

bioRxiv2019

Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state

Receptor tyrosine kinases (RTKs), the largest class of transmembrane cell surface receptors, initiate signalling pathways which regulate diverse cellular processes. On activation these receptors rapidly recruit multiple downstream effector proteins to moderate affinity tyrosyl phosphate (pY) binding sites. However, the mechanism for expedient downstream effector protein recruitment via random molecular diffusion through the cytoplasm is not fully understood. One way in which the probabilistic outcome associated with random diffusion could be alleviated is through localized accumulation of high effective concentrations of signalling proteins in discrete pools in the cell (1). The inclusion of interacting proteins into liquid-liquid phase-separated (LLPS), membraneless protein droplets maintains functionally relevant proteins at high concentrations in a liquid phase at the required point of action, enhancing equilibrium binding and enzyme activity (2-6). These LLPS states have been associated with a wide range of cellular functions including regulation of signalling through, for example, nephrin (7, 8), the T-cell receptor (9), mTOR (10), and Sos-Ras (11), however, whether LLPS extends to RTK-mediated signal transduction has not been investigated. Here, we show that an RTK, fibroblast growth factor receptor 2 (FGFR2), forms a signalling competent LLPS state with two downstream effectors, a tandem Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (Shp2), and 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma 1 (Plc{gamma}1). We show that these proteins assemble into a ternary complex which exploits LLPS condensation to simultaneously modulate kinase, phosphatase and phospholipase activities. Therefore, LLPS formation ensures that the requirement for prolonged, high-fidelity signalling is achieved. Additional RTKs also form LLPS with their downstream effectors, suggesting that formation of biological condensates is a key organising principle of RTK-mediated signalling, with broad implications for further mechanistic studies as well as therapeutic intervention.

cell biology↗

bioRxiv2019

Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Alzheimers disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. A{beta} species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how A{beta} plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that A{beta} plaques grow faster in the earlier stages of the disease and if their initial area is > 500 {micro}m2; this may be due to deposition occurring in the diffuse part of the plaque. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre-but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

neuroscience↗

bioRxiv2019

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models.

The onset and progression of Alzheimers disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and accumulation of {beta}-amyloid (A{beta}) in the neocortex. Despite recent success in identifying genetic risk factors for AD the transcriptional mechanisms involved in disease progression are not fully understood. We used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the development of both tau and amyloid pathology. Using highly-parallel RNA sequencing we profiled transcriptional variation in the entorhinal cortex at four time points identifying robust genotype-associated differences in entorhinal cortex gene expression in both models. We quantified neuropathological burden across multiple brain regions in the same individual mice, identifying widespread changes in gene expression paralleling the development of tau pathology in rTg4510 mice. Differentially expressed transcripts included genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in GWAS and exome-sequencing studies of late-onset sporadic AD. Systems-level analyses identified discrete co-expression networks associated with the progressive accumulation of tau, with these enriched for genes and pathways previously implicated in the neuro-immunological and neurodegenerative processes driving AD pathology. Finally, we report considerable overlap between tau-associated networks and AD-associated co-expression modules identified in the human cortex. Our data provide further support for an immune-response component in the accumulation of tau, and reveal novel molecular pathways associated with the progression of AD neuropathology.

genomics↗

bioRxiv2018

Attenuating the DNA damage response to double strand breaks is neuroprotective

DNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. Persistent activation of the DNA damage response in response to double strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage response might be neuroprotective. Here, we show that attenuating the DNA damage response by targeting the meiotic recombination 11, Rad50, Nijmegen breakage syndrome 1 complex, which is involved in double strand break recognition, is neuroprotective in three neurodegeneration models in Drosophila and prevents A{beta}1-42-induced loss of synapses in embryonic hippocampal neurons. Attenuating the DNA damage response after optic nerve injury is also neuroprotective to retinal ganglion cells and promotes dramatic regeneration of their neurites both in vitro and in vivo. Dorsal root ganglion neurons similarly regenerate when the DNA damage response is targeted in vitro and in vivo and this strategy also induces significant restoration of lost function after spinal cord injury. We conclude that muting the DNA damage response in the nervous system is neuroprotective in multiple neurological disorders. Our results point to new therapies to maintain or repair the nervous system.

neuroscience↗