Hippocampus of the APPNL-G-F mouse model of Alzheimer’s disease exhibits region-specific tissue softening concomitant with elevated astrogliosis

Widespread neurodegeneration, enlargement of cerebral ventricles, and atrophy of cortical and hippocampal brain structures are classic hallmarks of Alzheimer’s disease (AD). Prominent macroscopic disturbances to the cytoarchitecture of the AD brain occur alongside changes in the mechanical properties of brain tissue, as reported in recent magnetic resonance elastography (MRE) measurements of human brain mechanics. Whilst MRE has many advantages, a significant shortcoming is its spatial resolution. Higher resolution “cellular scale” assessment of the mechanical alterations to brain regions involved in memory formation, such as the hippocampus, could provide fresh new insight into the etiology of AD. Characterization of brain tissue mechanics at the cellular length scale is the first stepping-stone to understanding how mechanosensitive neurons and glia are impacted by neurodegenerative disease-associated changes in their microenvironment. To provide insight into the microscale mechanics of aging brain tissue, we measured spatiotemporal changes in the mechanical properties of the hippocampus using high resolution atomic force microscopy (AFM) indentation tests on acute brain slices from young and aged wild-type mice and the APPNL–G–F mouse model. Several hippocampal regions in APPNL–G–F mice are significantly softer than age-matched wild-types, notably the dentate granule cell layer and the CA1 pyramidal cell layer. Interestingly, regional softening coincides with an increase in astrocyte reactivity, suggesting that amyloid pathology-mediated alterations to the mechanical properties of brain tissue may impact the function of mechanosensitive astrocytes. Our data also raise questions as to whether aberrant mechanotransduction signaling could impact the susceptibility of neurons to cellular stressors in their microenvironment

Mechanobiology of the brain in ageing and Alzheimer's disease

Just as the epigenome, the proteome and the electrophysiological properties of a cell influence its function, so too do its intrinsic mechanical properties and its extrinsic mechanical environment. This is especially true for neurons of the central nervous system (CNS) as long‐term maintenance of synaptic connections relies on efficient axonal transport machinery and structural stability of the cytoskeleton. Recent reports suggest that profound physical changes occur in the CNS microenvironment with advancing age which, in turn, will impact highly mechanoresponsive neurons and glial cells. Here, we discuss the complex and inhomogeneous mechanical structure of CNS tissue, as revealed by recent mechanical measurements on the brain and spinal cord, using techniques such as magnetic resonance elastography and atomic force microscopy. Moreover, ageing, traumatic brain injury, demyelination and neurodegeneration can perturb the mechanical properties of brain tissue and trigger mechanobiological signalling pathways in neurons, glia and cerebral vasculature. It is, therefore, very likely that significant changes in cell and tissue mechanics contribute to age‐related cognitive decline and deficits in memory formation which are accelerated and magnified in neurodegenerative states, such as Alzheimer's disease. Importantly, we are now beginning to understand how neuronal and glial cell mechanics and brain tissue mechanobiology are intimately linked with neurophysiology and cognition

Comparison of Supine and Vertical Bioimpedance Measurements in Young Adults

Topics in Exercise Science and Kinesiology Volume 3: Issue 1, Article 11, 2022. Bioelectrical impedance analysis (BIA) methods estimate health parameters such as phase angle (PhA) and body fat percentage (%BF) from various positional and electrode configurations. PhA and %BF are known biological markers of cellular and physical health, respectively, and can be used to predict various health-related conditions and therefore require accurate assessment. The purpose of this study was to evaluate the effect of body position during BIA by investigating the difference and agreement between PhA and %BF using RJL (supine) and InBody (vertical) analyzers. Thirty-eight young adults (23.4±4.1 yrs.) volunteered and underwent body composition assessments by both analyzers. Difference and agreement in assessments of PhA and %BF between analyzers were assessed using paired samples t-tests and Lin’s concordance correlation coefficient (rc), respectively. RJL’s PhA (7.15±0.84°) exceeded InBody’s (6.11±0.74°), p\u3c0.001, and had poor agreement (rc =0.47). RJL’s %BF (23.0±6.8%) was similar to InBody’s (23.1±7.4%), p=0.813, and had substantial agreement (rc =0.95). Both analyzers estimated %BF similarly and may be interchangeable for this purpose, thus demonstrating no effect of body position on the estimation of %BF with these BIA devices. An individual\u27s PhA may be underestimated if measured in the vertical position and compared to supine reference values. Current reference values for PhA are based on measurements in the supine position, so until vertical reference values of PhA are available, caution is urged when interpreting PhA from vertical BIA assessments

Hippocampus of the APPNL–G–F mouse model of Alzheimer’s disease exhibits region-specific tissue softening concomitant with elevated astrogliosis

Widespread neurodegeneration, enlargement of cerebral ventricles, and atrophy of cortical and hippocampal brain structures are classic hallmarks of Alzheimer’s disease (AD). Prominent macroscopic disturbances to the cytoarchitecture of the AD brain occur alongside changes in the mechanical properties of brain tissue, as reported in recent magnetic resonance elastography (MRE) measurements of human brain mechanics. Whilst MRE has many advantages, a significant shortcoming is its spatial resolution. Higher resolution “cellular scale” assessment of the mechanical alterations to brain regions involved in memory formation, such as the hippocampus, could provide fresh new insight into the etiology of AD. Characterization of brain tissue mechanics at the cellular length scale is the first stepping-stone to understanding how mechanosensitive neurons and glia are impacted by neurodegenerative disease-associated changes in their microenvironment. To provide insight into the microscale mechanics of aging brain tissue, we measured spatiotemporal changes in the mechanical properties of the hippocampus using high resolution atomic force microscopy (AFM) indentation tests on acute brain slices from young and aged wild-type mice and the APPNL–G–F mouse model. Several hippocampal regions in APPNL–G–F mice are significantly softer than age-matched wild-types, notably the dentate granule cell layer and the CA1 pyramidal cell layer. Interestingly, regional softening coincides with an increase in astrocyte reactivity, suggesting that amyloid pathology-mediated alterations to the mechanical properties of brain tissue may impact the function of mechanosensitive astrocytes. Our data also raise questions as to whether aberrant mechanotransduction signaling could impact the susceptibility of neurons to cellular stressors in their microenvironment

Hippocampus of the APP NL–G–F mouse model of Alzheimer’s disease exhibits region-specific tissue softening concomitant with elevated astrogliosis

Widespread neurodegeneration, enlargement of cerebral ventricles, and atrophy of cortical and hippocampal brain structures are classic hallmarks of Alzheimer’s disease (AD). Prominent macroscopic disturbances to the cytoarchitecture of the AD brain occur alongside changes in the mechanical properties of brain tissue, as reported in recent magnetic resonance elastography (MRE) measurements of human brain mechanics. Whilst MRE has many advantages, a significant shortcoming is its spatial resolution. Higher resolution “cellular scale” assessment of the mechanical alterations to brain regions involved in memory formation, such as the hippocampus, could provide fresh new insight into the etiology of AD. Characterization of brain tissue mechanics at the cellular length scale is the first stepping-stone to understanding how mechanosensitive neurons and glia are impacted by neurodegenerative disease-associated changes in their microenvironment. To provide insight into the microscale mechanics of aging brain tissue, we measured spatiotemporal changes in the mechanical properties of the hippocampus using high resolution atomic force microscopy (AFM) indentation tests on acute brain slices from young and aged wild-type mice and the APPNL–G–F mouse model. Several hippocampal regions in APPNL–G–F mice are significantly softer than age-matched wild-types, notably the dentate granule cell layer and the CA1 pyramidal cell layer. Interestingly, regional softening coincides with an increase in astrocyte reactivity, suggesting that amyloid pathology-mediated alterations to the mechanical properties of brain tissue may impact the function of mechanosensitive astrocytes. Our data also raise questions as to whether aberrant mechanotransduction signaling could impact the susceptibility of neurons to cellular stressors in their microenvironment

The sphingosine 1-phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus

The small-molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1-phosphate (S1P) analogue currently used to treat relapsing-remitting multiple sclerosis in both adults and children. FTY720 can cross the blood-brain barrier (BBB) and, over time, accumulate in lipid-rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor-mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry-based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy-phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up-regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down-regulated. FTY720 also modulated anxiety-like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system

Risk of cerebrovascular disease among 13,457 five‐year survivors of childhood cancer: a population based cohort study

Survivors of childhood cancer treated with cranial irradiation are at risk of cerebrovascular disease (CVD), but the risks beyond age 50 are unknown. In all, 13457 survivors of childhood cancer included in the population‐based British Childhood Cancer Survivor Study cohort were linked to Hospital Episode Statistics data for England. Risk of CVD related hospitalisation was quantified by standardised hospitalisation ratios (SHRs), absolute excess risks and cumulative incidence. Overall, 315 (2.3%) survivors had been hospitalised at least once for CVD with a 4‐fold risk compared to that expected (95% confidence interval [CI]: 3.7‐4.3). Survivors of a central nervous system (CNS) tumour and leukaemia treated with cranial irradiation were at greatest risk of CVD (SHR = 15.6, 95% CI: 14.0‐17.4; SHR = 5.4; 95% CI: 4.5‐6.5, respectively). Beyond age 60, on average, 3.1% of CNS tumour survivors treated with cranial irradiation were hospitalised annually for CVD (0.4% general population). Cumulative incidence of CVD increased from 16.0% at age 50 to 26.0% at age 65 (general population: 1.4‐4.2%). In conclusion, among CNS tumour survivors treated with cranial irradiation, the risk of CVD continues to increase substantially beyond age 50 up to at least age 65. Such survivors should be: counselled regarding this risk; regularly monitored for hypertension, dyslipidaemia and diabetes; advised on life‐style risk behaviours. Future research should include the recall for counselling and brain MRI to identify subgroups that could benefit from pharmacological or surgical intervention and establishment of a case‐control study to comprehensively determine risk‐factors for CVD

The sphingosine 1‐phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus

The small‐molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1‐phosphate (S1P) analogue currently used to treat relapsing–remitting multiple sclerosis in both adults and children. FTY720 can cross the blood–brain barrier (BBB) and, over time, accumulate in lipid‐rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor‐mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry‐based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy‐phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up‐regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down‐regulated. FTY720 also modulated anxiety‐like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use.Fil: Eppley, Timothy M.. San Diego Zoo Wildlife Alliance; Estados Unidos. Portland State University; Estados UnidosFil: Hoeks, Selwyn. Radboud Universiteit Nijmegen; Países BajosFil: Chapman, Colin A.. University of KwaZulu-Natal; Sudáfrica. Wilson Center; Estados Unidos. Northwest University; China. The George Washington University; Estados UnidosFil: Ganzhorn, Jörg U.. Universitat Hamburg; AlemaniaFil: Hall, Katie. Sedgwick County Zoo; Estados UnidosFil: Owen, Megan A.. San Diego Zoo Wildlife Alliance; Estados UnidosFil: Adams, Dara B.. Humboldt State University; Estados Unidos. Ohio State University; Estados UnidosFil: Allgas, Néstor. Asociación Neotropical Primate Conservation Perú; PerúFil: Amato, Katherine R.. Northwestern University; Estados UnidosFil: Andriamahaihavana, McAntonin. Université D'antananarivo; MadagascarFil: Aristizabal, John F.. Universidad Autónoma de Ciudad Juárez; México. Universidad de los Andes; ColombiaFil: Baden, Andrea L.. City University of New York; Estados Unidos. New York Consortium In Evolutionary Primatology; Estados UnidosFil: Balestri, Michela. Oxford Brookes University (oxford Brookes University);Fil: Barnett, Adrian A.. University Of Roehampton; Reino Unido. Universidade Federal de Pernambuco; BrasilFil: Bicca Marques, Júlio César. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Bowler, Mark. University Of Suffolk; Reino Unido. San Diego Zoo Wildlife Alliance; Estados UnidosFil: Boyle, Sarah A.. Rhodes College; Estados UnidosFil: Brown, Meredith. University of Calgary; CanadáFil: Caillaud, Damien. University of California at Davis; Estados UnidosFil: Calegaro Marques, Cláudia. Universidade Federal do Rio Grande do Sul; BrasilFil: Campbell, Christina J.. California State University Northridge (calif. State Univ. Northridge);Fil: Campera, Marco. Oxford Brookes University (oxford Brookes University);Fil: Campos, Fernando A.. University of Texas at San Antonio; Estados UnidosFil: Cardoso, Tatiane S.. Museu Paraense Emílio Goeldi; BrasilFil: Carretero Pinzón, Xyomara. Proyecto Zocay; ColombiaFil: Champion, Jane. University of Calgary; CanadáFil: Chaves, Óscar M.. Universidad de Costa Rica; Costa RicaFil: Chen Kraus, Chloe. University of Yale; Estados UnidosFil: Colquhoun, Ian C.. Western University; CanadáFil: Dean, Brittany. University of Calgary; CanadáFil: Kowalewski, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Centro de Ecología Aplicada del Litoral. Universidad Nacional del Nordeste. Centro de Ecología Aplicada del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia". Estación Biológica de Usos Múltiples (Sede Corrientes); Argentin

Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia

Funder: Cure Alzheimer's Fund; doi: http://dx.doi.org/10.13039/100007625Funder: UK Dementia Research Institute (GB)Funder: Censejo Nacional de Ciencia Tecnilogia (MX)Funder: Alzheimerfonden; doi: http://dx.doi.org/10.13039/501100008599Funder: Dolby Family FundAbstract: Background: Microglia are active modulators of Alzheimer’s disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. Methods: AppNL-F and AppNL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer’s disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. Results: Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in AppNL-F mice but was not evident in AppNL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. Conclusions: Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer’s disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer’s disease