Biology subjects

Metaxas, A.

Publications and source records attributed to Metaxas, A..

6 recordsLinked to original sources

bioRxiv2025

Age-specific Aβ-Tau interactions underlie spatial memory deficits in an APP/PS1 amyloidosis model

BackgroundAmyloid-{beta} (A{beta}) and tau pathology are key molecular hallmarks of Alzheimers disease (AD), yet how their interaction contributes to cognitive decline remains unclear. We investigated the relationship between A{beta} burden, tau pathology, presynaptic density, and spatial learning and memory in the APPswe/PSEN1{Delta}E9 (APP/PS1) transgenic (TG) mouse model of amyloidosis. MethodsSpatial learning and memory were assessed with the Barnes maze test in male TG and wild-type (WT) littermate mice, aged 6, 12, and 18 months. Gross visual function was assessed indirectly in 18-month-old animals using the light/dark exploration test. Brains were collected for autoradiography of tau pathology and presynaptic density with [18F]Flortaucipir and [3H]UCB-J, respectively, while A{beta} plaque load was measured by immunohistochemistry. Correlation and linear mixed-effects regression analyses were used to assess relationships between behavioral and pathological measures. ResultsAPP/PS1 mice showed normal cognitive performance at 6 months, a selective long-term memory deficit at 12 months, and severe impairments in learning and retention at 18 months, independent of visual confounds. Age-dependent increases in [18F]Flortaucipir binding and A{beta} plaque load were observed in all brain regions of TG compared to WT mice, whereas [3H]UCB-J binding was increased in a region-dependent manner in 18-month-old TG vs. WT animals. Barnes maze performance during the final day of testing correlated negatively with both A{beta} and tau pathology across all areas examined. Linear regression revealed a significant association between tau and age and between tau and A{beta} in the cortex, indicating that memory decline in ageing TG mice was driven by the combined effects of these pathologies. ConclusionsDeficits in memory retention precede impairments in task learning performance in APP/PS1 mice. Spontaneous tau accumulation contributes to the progressive cognitive decline, capturing key aspects of the A{beta}-tau interaction observed in human AD.

neuroscience↗

bioRxiv2024

Serotonin-2B receptor (5-HT2BR) expression and binding in the brain of ageing APPswe/PS1de9 transgenic mice and in human Alzheimer's disease brain tissue

Although evidence of dysregulation in central serotonergic signaling is widespread in Alzheimers disease (AD), relatively little is known about the specific involvement of the serotonin-2B receptor (5-HT2BR) subtype. Here, we assessed 5-HT2BR expression and binding in brain tissue from APPswe/PS1dE9 transgenic (TG) mice and AD patients. 5-HT2BR mRNA was measured by RT-qPCR in 3-to >18-month-old TG and wild-type (WT) littermate mice (n=3-8), and in middle frontal gyrus samples from female, AD and control subjects (n=7-10). The density of 5-HT2BRs was measured by autoradiography using 1 nM [3H]RS127445 and 1 M LY266097. In both mouse and human samples, 5-HT2BR mRNA was detectable after 33 amplification cycles. Levels in WT mice, not TG mice, increased with age, and were higher in AD patients compared to control subjects. [3H]RS127445 binding was low in the mouse brain, detected after 3 months of age. 5-HT2BR density was overall lower in the hippocampus of TG compared to WT mice. Specific binding was too low to be reliably quantified in the human samples. These data provide evidence of a different 5-HT2BR expression and binding in the APPswe/PS1dE9 TG model of AD and AD patients. Studies investigating the functional involvement of the 5-HT2BR in AD are warranted.

neuroscience↗

bioRxiv2024

A blueprint for national assessments of the blue carbon capacity of kelp forests applied to Canadas coastline

Kelp forests offer substantial carbon fixation, with the potential to contribute to natural climate solutions (NCS). However, to be included in national NCS inventories, governments must first quantify the kelp-derived carbon stocks and fluxes leading to carbon sequestration. Here, we present a blueprint for assessing the national carbon sequestration capacity of kelp forests in which data synthesis and Bayesian hierarchical modelling enable estimates of kelp forest carbon production, storage, and export capacity from limited data. Applying this blueprint to Canadas extensive coastline, we find kelp forests store an estimated 1.4 Tg C in short-term biomass and produce 3.1 Tg C yr-1 with modest carbon fluxes to the deep ocean. Arctic kelps had the highest carbon stocks and production capacity, while Pacific kelps had greater carbon fluxes overall due to their higher productivity and export rates. Our transparent, reproducible blueprint represents an important step towards accurate carbon accounting for kelp forests.

ecology↗

bioRxiv2023

A systematic review and meta-analysis of tau phosphorylation in mouse models of familial Alzheimer's disease

BackgroundTransgenic models of familial Alzheimers disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (A{beta})-induced pathology. Here, we sought to evaluate the levels of phosphorylated tau (p-tau) protein, and explore potential age-related variations in the hyperphosphorylation of tau, in mouse models of cerebral amyloidosis. MethodsThe PubMed and Scopus databases were searched for studies measuring soluble p-tau in 5xFAD, APPswe/PSEN1de9, J20 and APP23 mice. Data were extracted and analyzed using standardized procedures. ResultsFor the 5xFAD model, the search yielded 36 studies eligible for meta-analysis. Levels of p-tau were higher in 5xFAD mice relative to control, a difference that was evident in both the carboxy-terminal (CT) and proline-rich (PR) domains of tau. Age negatively moderated the effects of genotype on CT domain phosphorylated tau, particularly in studies using hybrid mice, female mice, and preparations from the cortex. For the APPswe/PSEN1de9 model, the search yielded 27 studies. Analysis showed tau hyperphosphorylation in transgenic vs. control animals, evident in both the CT and PR regions of tau. Age positively moderated the effects of genotype on PR domain phosphorylated tau in the cortex of APPswe/PSEN1de9 mice. A meta-analysis was not performed for the J20 and APP23 models, due to the limited number of studies measuring p-tau levels in these mice (<10 studies). ConclusionsAlthough tau is hyperphosphorylated in both 5xFAD and APPswe/PSEN1de9 mice, the effects of ageing on p-tau are contingent upon the mouse model being examined. These observations emphasize the importance of tailoring model selection to the appropriate disease stage when assessing the relationship between A{beta} and tau, and suggest that there are optimal intervention points for the administration of both anti-amyloid and anti-tau therapies.

neuroscience↗

bioRxiv2018

Tauopathy in the APPswe/PS1ΔE9 mouse model of familial Alzheimer’s disease

Despite compelling evidence that the accumulation of amyloid-beta (A{beta}) promotes cortical MAPT (tau) aggregation in familial and idiopathic Alzheimers disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. The absence of neurofibrillary lesions in amyloidosis mice remains a challenge for the amyloidocentric paradigm of AD pathogenesis. It has resulted in the generation of transgenic mice harboring mutations in their tau gene, which may be inappropriate for studying a disease with no known TAU mutations, such as AD. Here, we have used APPswe/PS1{Delta}E9 mice to show that tau pathology can develop spontaneously in murine models of familial AD. Tauopathy was abundant around A{beta} deposits, with Gallyas- and thioflavin-S-positive perinuclear inclusions accumulating in the APPswe/PS1{Delta}E9 cortex by 18 months of age. Age-dependent increases in Gallyas signal correlated positively with binding levels of the paired helical filament (PHF) ligand [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Tandem mass tag proteomics identified sequences of hyperphosphorylated tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Human frontal gyrus tissue was used to validate these findings, revealing primarily quantitative differences between the tauopathy observed in AD patient vs. transgenic mouse tissue. Levels of tau mRNA were not different between APPswe/PS1{Delta}E9 and littermate control animals. As physiological levels of endogenous, wild-type tau aggregate secondarily to A{beta} in transgenic mice, this study demonstrates that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.

neuroscience↗

bioRxiv2018

Operationalizing ecological connectivity in spatial conservation planning with Marxan Connect

O_LIGlobally, protected areas are being established to protect biodiversity and to promote ecosystem resilience. The typical spatial conservation planning process leading to the creation of these protected areas focuses on representation and replication of ecological features, often using decision support systems such as Marxan. Unfortunately, Marxan currently requires manual input or specialised scripts to explicitly consider ecological connectivity, a property critical to metapopulation persistence and resilience.\nC_LIO_LI\"Marxan Connect\" is a new open source, open access Graphical User Interface (GUI) designed to assist conservation planners in the systematic operationalization of ecological connectivity in protected area network planning.\nC_LIO_LIMarxan Connect is able to incorporate estimates of demographic connectivity (e.g. derived from tracking data, dispersal models, or genetics) or structural landscape connectivity (e.g. isolation by resistance). This is accomplished by calculating metapopulation-relevant connectivity metrics (e.g. eigenvector centrality) and treating those as conservation features, or using the connectivity data as a spatial dependency amongst sites to be included in the prioritization process.\nC_LIO_LIMarxan Connect allows a wide group of users to incorporate directional ecological connectivity into conservation plans. The least-cost conservation solutions provided by Marxan Connect, combined with ecologically relevant post-hoc testing, are more likely to support persistent and resilient metapopulations (e.g. fish stocks) and provide better protection for biodiversity than if connectivity is ignored.\nC_LI

ecology↗