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A study carried out by the research group led by Prof Zaccolo provides novel insight into how the heart reacts to the fight-or-flight response to stress
Alzheimer's disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons.
Tau accumulation is closely related to cognitive symptoms in Alzheimer's disease (AD). However, the cellular drivers of tau-dependent decline of memory-based cognition remain elusive. Here, we employed in vivo Neuropixels and patch-clamp recordings in mouse models and demonstrate that tau, independent of β-amyloid, selectively debilitates complex-spike burst firing of CA1 hippocampal neurons, a fundamental cellular mechanism underpinning learning and memory. Impaired bursting was associated with altered hippocampal network activities that are coupled to burst firing patterns (i.e., theta rhythms and high-frequency ripples) and was concurrent with reduced neuronal expression of CaV2.3 calcium channels, which are essential for burst firing in vivo. We subsequently identify soluble high molecular weight (HMW) tau, isolated from human AD brain, as the tau species responsible for suppression of burst firing. These data provide a cellular mechanism for tau-dependent cognitive decline in AD and implicate a rare species of intracellular HMW tau as a therapeutic target.
Chronic silencing of Drd1a-Cre+ neurons impairs dopaminergic-driven cortical activation.
In the somatosensory cortex of transgenic mice, Cre-recombinase is expressed under the control of the dopamine receptor D1 (Drd1a) promoter in lower layer 6. These neurons selectively project to the higher-order thalamic nuclei and participate in the cortico-thalamo-cortical loops involved in sensory processing and stimulus representation. However, the role of dopaminergic modulation in activating this neuronal population during cortical arousal remains poorly understood. In this study, we examined the effects of D1 (SKF-81297) and D2 (Quinpirole) receptor agonists on cortical network activation. We further investigated the consequences of silencing these neurons using a Snap25 conditional knockout mouse model. We report a decrease in cellular and neuronal density in the subplate/L6b with normal development from P8 to adulthood. Conversely, the density of Drd1a-Cre+ neurons goes up in Snap25 cKO brains when comparing the same ages. Moreover, we observe that silencing of Drd1a-Cre+ neurons has no effect on microglial cells. Our results demonstrate that both D1 and D2 agonists require the Drd1a-Cre+ neurons to modulate cortical activity effectively. Our study provides new insights into the fundamental role of Drd1a-Cre+ neurons in cortical activation and sensory processing.
Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.
We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.
The profile of gastrointestinal dysfunction in prodromal to late-stage Parkinson's disease.
Gastrointestinal dysfunction (GID) may play a key role in Parkinson's disease (PD) but its relationship with disease progression remains unclear. We recruited 404 PD cases, 37 iRBD (isolated REM Sleep Behaviour Disorder) and 105 controls. Participants completed the Gastrointestinal Dysfunction Scale for PD (GIDS-PD) and standardised disease severity assessments. Whole gut transit time (WGTT) was measured by ingestion of blue dye and recorded time to blue stools appearance ('Blue Poop Challenge') in a subset of PD cases. Gastrointestinal symptoms were more common and prevalent in iRBD and PD versus controls, and WGTT was significantly higher in PD versus controls. After adjustment for confounding factors, disease stage was not a significant predictor of GIDS-PD Constipation or Bowel Irritability scores. Longitudinal assessment of GIDS-PD scores and WGTT confirmed stability over a 4 year period. Bowel dysfunction may be a phenotypic feature in a subset of Parkinson's with implications for patient stratification and management.
GPCR signaling via cAMP nanodomains.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, mediating essential physiological responses through diverse intracellular signaling pathways. When coupled to Gs or Gi proteins, GPCR modulates the synthesis of 3'-5'-cyclic adenosine monophosphate (cAMP), which governs a wide array of processes, ranging from cellular growth and survival to metabolic regulation. Studies have highlighted that cAMP is not uniformly distributed within cells but instead is compartmentalized into highly localized nanodomains. These nanodomains, mostly regulated by phosphodiesterases (PDEs), play a critical role in enabling signal precision and functional effects that are specific to individual stimuli. GPCRs can initiate distinct cAMP responses based on their localization within the cell, with evidence showing that both receptors resident at the plasma membrane and intracellular receptors-including endosomal, Golgi, and nuclear GPCRs-elicit unique cAMP signaling profiles. This review examines the mechanisms underlying GPCR signaling through cAMP nanodomains. We focus on the role of PDE-mediated cAMP degradation in shaping local cAMP signals, the emerging views on mechanisms that may contribute to signal compartmentalization, and the role of intracellular membrane compartments. By exploring these aspects, we aim to highlight the complexity of GPCR signaling networks and illustrate some of the implications for the regulation of cellular function.
Computational modelling of biological systems now and then: revisiting tools and visions from the beginning of the century
Since the turn of the millennium, computational modelling of biological systems has evolved remarkably and sees matured use spanning basic and clinical research. While the topic of the peri-millennial debate about the virtues and limitations of ‘reductionism and integrationism’ seems less controversial today, a new apparent dichotomy dominates discussions: mechanistic versus data-driven modelling. In light of this distinction, we provide an overview of recent achievements and new challenges with a focus on the cardiovascular system. Attention has shifted from generating a universal model of the human to either models of individual humans (digital twins) or entire cohorts of models representative of clinical populations to enable in silico clinical trials. Disease-specific parametrization, inter-individual and intra-individual variability, uncertainty quantification as well as interoperable, standardized and quality-controlled data are important issues today, which call for open tools, data and metadata standards, as well as strong community interactions. The quantitative, biophysical and highly controlled approach provided by in silico methods has become an integral part of physiological and medical research. In silico methods have the potential to accelerate future progress also in the fields of integrated multi-physics modelling, multi-scale models, virtual cohort studies and machine learning beyond what is feasible today. In fact, mechanistic and data-driven modelling can complement each other synergistically and fuel tomorrow’s artificial intelligence applications to further our understanding of physiology and disease mechanisms, to generate new hypotheses and assess their plausibility, and thus to contribute to the evolution of preventive, diagnostic and therapeutic approaches. This article is part of the theme issue ‘Science into the next millennium: 25 years on’.
ATR-hippo drives force signaling to nuclear F-actin and links mechanotransduction to neurological disorders.
The mechanical environment is sensed through cell-matrix contacts with the cytoskeleton, but how signals transit the nuclear envelope to affect cell fate decisions remains unknown. Nuclear actin coordinates chromatin motility during differentiation and genome maintenance, yet it remains unclear how nuclear actin responds to mechanical force. The DNA-damage kinase ataxia telangiectasia and Rad3-related protein (ATR) translocates to the nuclear envelope to protect the nucleus during cell motility or compression. Here, we show that ATR drives nuclear actin assembly via recruitment of Filamin-A to the inner nuclear membrane through binding of the hippo pathway scaffold and ATR substrate, RASSF1A. Moreover, we demonstrate how germline RASSF1 mutation disables nuclear mechanotransduction resulting in cerebral cortex thinning and associates with common psychological traits. Thus, defective mechanical-regulated pathways may contribute to complex neurological disorders.
Redefining respiratory sinus arrhythmia as respiratory heart rate variability: an international Expert Recommendation for terminological clarity.
The variation of heart rate in phase with breathing, known as 'respiratory sinus arrhythmia' (RSA), is a physiological phenomenon present in all air-breathing vertebrates. RSA arises from the interaction of several physiological mechanisms but is primarily mediated by rhythmic changes in cardiac parasympathetic (vagal) activity, increasing heart rate during inspiration and decreasing heart rate during expiration. RSA amplitude is an indicator of autonomic and cardiac health; RSA is diminished or absent in common pathological conditions such as chronic heart failure and hypertension. In this Expert Recommendation, we argue that the term 'RSA', although historically important, is semantically inaccurate and carries misleading pathological connotations, contributing to misunderstanding and misinterpretation of the origin and the physiological importance of the phenomenon. We propose replacing 'RSA' with the term 'respiratory heart rate variability' (RespHRV), which avoids pathological connotations and emphasizes the specific respiratory contribution to heart rate variability. We clarify that RespHRV encompasses respiratory-related heart rate variations in both the low-frequency and high-frequency bands traditionally defined in heart rate variability analysis, and that its amplitude should not be misconstrued as a measure of vagal tone. Adopting the proposed term 'RespHRV' is expected to unify understanding and stimulate further experimental and clinical research into the physiological mechanisms and functional importance of this phenomenon.
A multi-color flow cytometric method for characterizing murine reticulated platelets using SYTO 13.
Reticulated platelets (RP) are immature platelets with heightened RNA content. An increased level of RP in the circulation is associated with various pathological conditions. In this study, we employed a novel flow cytometry approach for RP detection in mice, utilizing the nucleic acid dye SYTO 13 in conjunction with a platelet-specific marker (anti-mouse CD42b-DyLight 649). The efficacy of SYTO 13 for RP identification was confirmed by higher circulating RP levels in platelet-depleted mice during the recovery phase (35% ± 13%) compared to untreated mice (11% ± 1%, n = 9, p
FoxO1-zDHHC4-CD36 S-Acylation Axis Drives Metabolic Dysfunction in Diabetes.
BACKGROUND: The fatty acid (FA) transporter CD36 (FA translocase/cluster of differentiation 36) is the gatekeeper of cardiac FA metabolism. Preferential localization of CD36 to the sarcolemma is one of the initiating cellular responses in the development of muscle insulin resistance and the type 2 diabetic heart. Posttranslational S-acylation controls protein trafficking, and in this study, we hypothesized that increased CD36 S-acylation may underpin the preferential sarcolemmal localization of CD36, driving metabolic and contractile dysfunction in diabetes. METHODS AND RESULTS: Type 2 diabetes increased cardiac CD36 S-acylation, CD36 sarcolemmal localization, FA oxidation rates, and triglyceride storage in the diabetic heart. CD36 S-acylation was increased in diabetic rats, db/db mice, diabetic pigs, and insulin-resistant human iPSC-derived cardiomyocytes, demonstrating conservation between species. The enzyme responsible for S-acylating CD36, zDHHC4, was transcriptionally upregulated in the diabetic heart, and genetic silencing of zDHHC4 using siRNA or lentiviral shRNA decreased CD36 S-acylation. We identified that zDHHC4 expression is under the regulation of the transcription factor FoxO (forkhead box O) 1, as FoxO1 binds to the promotor of zDHHC4 and induces its transcription, as assessed using chromatin immunoprecipitation-seq, chromatin immunoprecipitation-quantitative PCR, luciferase assays, and siRNA silencing. Diabetic mice with cardiomyocyte-specific FoxO1 deletion had decreased cardiac zDHHC4 expression and decreased CD36 S-acylation, which was further confirmed using diabetic mice treated with the FoxO1 inhibitor AS1842856. Pharmacological inhibition of zDHHC enzymes in diabetic hearts decreased CD36 S-acylation, sarcolemmal CD36 content, FA oxidation rates, and triglyceride storage, culminating in improved cardiac function in diabetes. Conversely, inhibiting the deacylating enzymes in control hearts increased CD36 S-acylation, sarcolemmal CD36 content, and FA metabolic rates in control hearts, recapitulating the metabolic phenotype seen in diabetic hearts. CONCLUSIONS: Activation of the FoxO1-zDHHC4-CD36 S-acylation axis in diabetes drives metabolic and contractile dysfunction in type 2 diabetic heart.
Working memory filtering at encoding and maintenance in healthy ageing, Alzheimer's and Parkinson's disease.
The differential impact on working memory (WM) performance of distractors presented at encoding or during maintenance was investigated in Alzheimer's Disease (AD), Parkinson's Disease (PD) patients, elderly (EHC) and young healthy controls (YHC), (n = 28 per group). Participants reported the orientation of an arrow from a set of either two or three items, with a distractor present either at encoding or at maintenance. MRI data with hippocampal volumes was also acquired. Mean absolute error and mixture model metrics i.e., memory precision, target detection, misbinding (swapping the features of an object with another probed item) and guessing were computed. EHC and PD patients showed good filtering abilities both at encoding and maintenance. However, AD patients exhibited significant filtering deficits specifically when the distractor appeared during maintenance. In healthy ageing there was a prominent decline in WM memory precision, whilst in AD lower target detection and higher guessing were the main sources of error. Conversely, PD was associated only with higher guessing rates. Hippocampal volume was significantly correlated with filtering during maintenance - but not at encoding. These findings demonstrate how healthy ageing and neurodegenerative diseases exhibit distinct patterns of WM impairment, including when filtering irrelevant material either at encoding and maintenance.