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bioRxiv2024

Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain

C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimers disease. TDP-43 phosphorylation at S403/S404, and especially at S409/S410, is in fact accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the proteins liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, in contrast to the unmodified protein, the phosphomimetic variants display a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically-relevant C-terminal phosphorylation on the LLPS of the TDP-43 in a more complex cellular environment. Statement of SignificanceProteinaceous inclusions composed of phosphorylated, C-terminal TDP-43 fragments have long been recognized as hallmarks of several neurodegenerative diseases, in particular amyotrophic lateral sclerosis and frontotemporal dementia. A rapidly growing number of studies indicate that these proteinopathies may be closely related to liquid-liquid phased separation (LLPS) of TDP-43, but the impact of phosphorylation on TDP-43 LLPS remains largely unexplored. In this study we used a combination of experimental methods and coarse-grained simulations to ascertain, in mechanistic terms, how phosphorylation at pathologically-critical C-terminal sites impacts liquid-liquid phase separation of the low complexity domain of TDP-43. Our results broaden our understanding of the mechanisms driving pathogenic process in these neurodegenerative diseases.

biophysics↗

bioRxiv2024

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Frontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased TDP-43 nucleus-to-cytosolic shuttling and p62/SQSTM1 accumulation, and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.

neuroscience↗

bioRxiv2024

Scale-free dynamics of cerebrospinal fluid regions is associated with Alzheimer's disease-related pathology

Cerebrospinal Fluid (CSF) clearance is one of the central mechanisms for removal of amyloid-{beta} (A{beta}) and tau proteins from the central nervous system that are closely linked to Alzheimers Disease (AD) pathology. Conventional functional imaging studies in AD have primarily focused on activities in the brain while ignoring macroscopic cerebrospinal fluid (CSF) activities. In the current study, we utilized a public dataset from the Alzheimers Disease Neuroimaging Initiative. Our analysis spanned both brain and cerebrospinal fluid (CSF) areas. We compared the scale-free dynamics in fMRI signals across three groups: cognitively normal individuals (CN), people with Alzheimers Disease (AD), and those with mild cognitive impairments (MCI). Scale-free dynamics are patterns of brain activity that remain consistent across different time scales. Our comparison focused on the Hurst exponent (H), a measure derived from detrended fluctuation analysis (DFA), to characterize these dynamics. This comparison revealed clusters in the fourth ventricle and subarachnoid space (medioventral channel along the spinal axis). In these CSF-filled structures, H was significantly higher in AD group comparing to CN. Moreover, H in these two clusters correlated with AD pathological biomarkers including CSF A{beta} and tau in the AD group. These findings suggested scale-free properties of macroscopic CSF flow as a potential imaging biomarker for AD. This biomarker can be readily acquired from common resting-state fMRI scans and therefore may be valuable for AD diagnosis.

neuroscience↗

bioRxiv2024

Secondary deficiency of neuraminidase 1 contributes to CNS pathology in neurological mucopolysaccharidoses via hypersialylation of brain glycoproteins

Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII are associated with lysosomal accumulation of heparan sulphate and manifest with neurological deterioration. Most of these neurological MPS currently lack effective treatments. Here, we report that, compared to controls, neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and in mouse models of MPS I, II, IIIA, IIIB and IIIC, but not of other neurological lysosomal disorders not presenting with heparan sulphate storage. We further show that accumulated heparan sulphate disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), {beta}-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) necessary to maintain enzyme activity, and that NEU1 deficiency is linked to partial deficiencies of GLB1 and GALNS in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brain samples of human MPS III patients and MPS IIIC mice implicated insufficient processing of brain N-linked sialylated glycans, except for polysialic acid, which was reduced in the brains of MPS IIIC mice. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of the excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1-/PSD95-positive puncta in cortical neurons derived from iPSC of an MPS IIIA patient. Together, our data demonstrate that heparan sulphate-induced secondary NEU1 deficiency and aberrant sialylation of glycoproteins implicated in synaptogenesis, memory, and behaviour constitute a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/587986v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@3905c3org.highwire.dtl.DTLVardef@1a9672corg.highwire.dtl.DTLVardef@b4911forg.highwire.dtl.DTLVardef@a3b190_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Reduced glucose supply during neonatal infection attenuates neurological and renal pathology via modulation of innate and Th1 immunity

BackgroundPremature infants are highly susceptible to infections that can lead to sepsis with life-threatening organ dysfunctions. The clinical practice of high parenteral glucose supply in preterm infants can exacerbate infection outcomes through excessive glycolysis-induced inflammatory response. This in turn can affect the health of vital preterm organs, including the brain and kidneys. We hypothesized that reducing glucose supply in infected preterm newborns may help protect against pathology in these two key organs. MethodsCaesarean-delivered preterm pigs were nourished with high or low parenteral glucose levels, infected with Staphylococcus epidermidis or saline, and cared for until 22h. Blood, brain, and kidney samples were collected at the end of the study for analyses. ResultsInfection led to multiple pathological changes, increased inflammation and tissue injury and dysfunction in both brain and kidneys of preterm piglets. Reduced glucose supply in infected animals alleviated neurological degradation, hyperemia and enhanced M2 microglial phenotype in the brain. This intervention also reduced plasma creatinine, renal edema, tubular vacuolization and dilatation. Multiple genes related to innate and Th1 immunity in both organs were highly correlated and dampened by reduced glucose supply, but there were clear signs that renal inflammation was closely connected to systemic inflammation while neuroinflammation was likely driven by immune response to the bacteria translocated into the brain. ConclusionReduced glucose supply can protect brain and kidney health in infected preterm neonates.

immunology↗

bioRxiv2024

Tau pathology leads to lonely non-traveling slow waves that mediate human memory impairment

Memory markedly declines with age, exaggerated in those with Alzheimers disease, yet the mechanisms are still not resolved. Here, we show that frontal lobe tau pathology in humans leads to impaired en masse unity and cortical traveling propagation of NREM slow waves, consequentially impairing memory retention. We elucidate these findings using PET tau brain imaging, and then replicate and extend them using AD pathology markers derived from lumbar puncture CSF in an independent clinical cohort. Thus, tau-associated memory deficits are not wholly direct, but indirectly mediated through consequential "lonely", non-traveling slow-wave events.

neuroscience↗

bioRxiv2024

Live-cell imaging of circular and long non-coding RNAs associated to FUS pathological aggregates by Pepper fluorescent RNA

Lately, important advancements in visualizing RNAs in fixed and live cells have been achieved. While mRNA imaging techniques are well-established, the development of effective methods for studying non-coding RNAs (ncRNAs) in living cells are still challenging but necessary, as they cover a variety of function and of intracellular localization, including highly dynamic processes like phase-transition, still poorly studied in vivo. Addressing this issue, we tagged two exemplary ncRNAs with the innovative fluorescent RNA (fRNA) Pepper. Specifically, we show circ-HDGFRP3 interaction with p-bodies, we recapitulate its recruitment in pathological FUS aggregates in a dynamic fashion and we super-resolve its distribution in such aggregates via Structured Illumination Microscopy. Moreover, we tracked the long non-coding RNA (lncRNA) nHOTAIRM1, a motor neurons-specific constituent of stress granules (SG), monitoring its behavior throughout the oxidative-stress response in physiological and pathological conditions. Overall, as fRNAs development advances, our work shows a successful use of Pepper for the monitoring of complex processes, as phase-transition, of paradigmatic molecules like circular RNAs (circRNAs) and lncRNAs with super-resolution potential in living mammalian cells.

molecular biology↗

bioRxiv2024

Oral citrate supplementation mitigates age-associated pathological intervertebral disc calcification in LG/J mice

Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. Here, we investigate the efficacy of long-term oral K3Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K3Citrate successfully reduced the incidence of disc calcification in LG/J mice without deleterious effects on vertebral bone structure, plasma chemistry, and locomotion. Notably, a positive effect on grip strength was evident in treated mice. Spectroscopic investigation of the persisting calcified nodules indicated K3Citrate did not alter the mineral composition and revealed that reactivation of an endochondral differentiation program in endplates may drive LG/J disc calcification. Importantly, K3Citrate reduced calcification incidence without altering the pathological endplate chondrocyte hypertrophy, suggesting mitigation of disc calcification primarily occurred through Ca2+ chelation, a conclusion supported by chondrogenic differentiation and Seahorse metabolic assays. Overall, this study underscores the therapeutic potential of K3Citrate as a systemic intervention strategy for disc calcification. TeaserOral citrate mitigates intervertebral disc mineralization in a mouse model of age-dependent spontaneous disc calcification.

cell biology↗

bioRxiv2024

Phosphoryl group wires stabilize pathological tau fibrils as revealed by multiple quantum spin counting NMR

Hyperphosphorylation of the protein tau is one of the biomarkers of neurodegenerative diseases in the category of tauopathies. However, the molecular level, mechanistic, role of this common post- translational modification (PTM) in enhancing or reducing the aggregation propensity of tau is unclear, especially considering that combinatorial phosphorylation of multiple sites can have complex, non-additive, effects on tau protein aggregation. Since tau proteins stack in register and parallel to elongate into pathological fibrils, phosphoryl groups from adjacent tau strands with 4.8 [A] separation must find an energetically favorable spatial arrangement. At first glance, this appears to be an unfavorable configuration due to the proximity of negative charges between phosphate groups from adjacent neighboring tau fibrils. However, this study tests a counterhypothesis that phosphoryl groups within the fibril core-forming segments favorably assemble into highly ordered, hydrogen-bonded, one-dimensionally extended wires under biologically relevant conditions. We selected two phosphorylation sites associated with neurodegeneration, serine 305 (S305p) and tyrosine 310 (Y310p), on a model tau peptide jR2R3-P301L (tau295-313) spanning the R2/R3 splice junction of tau, that readily aggregate into a fibril with characteristics of a seed-competent mini prion. Using multiple quantum spin counting (MQ-SC) by 31P solid-state NMR of phosphorylated jR2R3-P301L tau peptide fibrils, enhanced by dynamic nuclear polarization, we find that at least six phosphorous spins must neatly arrange in 1D within fibrils or in 2D within a protofibril to yield the experimentally observed MQ-coherence orders of four. We found that S305p stabilizes the tau fibrils and leads to more seeding-competent fibrils compared to jR2R3 P301L or Y310p. This study introduces a new concept that phosphorylation of residues within a core forming tau segment can mechanically facilitate fibril registry and stability due a hitherto unrecognized role of phosphoryl groups to form highly ordered, extended, 1D wires that stabilize pathological tau fibrils. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/606685v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@eb7176org.highwire.dtl.DTLVardef@1661a3forg.highwire.dtl.DTLVardef@4548dforg.highwire.dtl.DTLVardef@b353b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Molecular Visualization of Neuronal TDP43 Pathology In Situ

Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, thereby enhancing RNA misprocessing due to the loss of nuclear TDP43, and engendering a cycle that ultimately leads to cell death. Here, we demonstrate that the addition of small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation, aberrant splicing, and degeneration in iPSC-derived neurons (iNeurons). By employing a tailored multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine the localization and aggregation of TDP43 in near-native conditions. We discover that mislocalized TDP43 accumulates and forms ordered fibrils within autophagosomes and lysosomes in iNeurons, as well as in ALS/FTLD patient tissue. We provide the first high-resolution snapshots of TDP43 aggregates in situ, delivering an unprecedented view of the earliest pathogenic events underlying ALS, FTLD, and related TDP43 proteinopathies.

neuroscience↗

bioRxiv2024

A robust evaluation of TDP-43, poly GP, cellular pathology, and behavior in a AAV-C9ORF72 (G4C2)66 mouse model

The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.

neuroscience↗

bioRxiv2024

How Alzheimer's Abeta propagates and triggers tau pathology in intact neurons

Alzheimers disease begins with A{beta} accumulation, progresses to tau aggregates and results in widespread neurodegeneration1-3. Simultaneous propagation of A{beta} aggregates from very limited to wide and distant brain regions is one of the outstanding events in the early stage. Here, we demonstrate that the neurovascular unit4,5 comprising capillaries and pericytes, the machinery supplying oxygen and glucose to neurons, is also the machinery for propagating effector molecules that impose Alzheimers pathologies on intact neurons. We discovered two distinct signaling cascades, one activated in capillary endothelial cells and the other in pericytes. At the origin of either cascade, we identified amylospheroid (ASPD)6,7, a highly toxic 30-mer assembly of A{beta}, and its sole target NKA38, a neuron-specific isoform of Na+,K+-ATPase9,10 but present in endothelial cells and pericytes. In endothelial cells, ASPD binding to NKA3 releases angiotensin II, which increases {beta}-secretase in intact neurons, causing a huge increase of A{beta}42and resultant accumulation. In pericytes, ASPD binding to NKA3 releases an unknown effector molecule that activates {delta}-secretase in intact neurons, further augmenting A{beta}42and producing pathogenic tau1-368 fragment. Thus, A{beta} and tau pathologies are directly linked. Stopping the signaling cascades near the origin by inhibiting ASPD-NKA3 interaction8 may provide a new therapeutic approach.

neuroscience↗

bioRxiv2024

Automatic diagnostics of electroencephalography pathology based on multi-domain feature fusion

Electroencephalography (EEG) serves as a practical auxiliary tool deployed to diagnose diverse brain-related disorders owing to its exceptional temporal resolution, non-invasive characteristics, and cost-effectiveness. In recent years, with the advancement of machine learning, automated EEG pathology diagnostics methods have flourished. However, most existing methods usually neglect the crucial spatial correlations in multi-channel EEG signals and the potential complementary information among different domain features, both of which are keys to improving discrimination performance. In addition, latent redundant and irrelevant features may cause overfitting, increased model complexity, and other issues. In response, we propose a novel feature-based framework designed to improve the diagnostic accuracy of multi-channel EEG pathology. This framework first applies a multi-resolution decomposition technique and a statistical feature extractor to construct a salient time-frequency feature space. Then, spatial distribution information is channel-wise extracted from this space to fuse with time-frequency features, thereby leveraging their complementarity to the fullest extent. Furthermore, to eliminate the redundancy and irrelevancy, a two-step dimension reduction strategy, including a lightweight multi-view time-frequency feature aggregation and a non-parametric statistical significance analysis, is devised to pick out the features with stronger discriminative ability. Comprehensive examinations of the Temple University Hospital Abnormal EEG Corpus V. 2.0.0 demonstrate that our proposal outperforms state-of-the-art methods, highlighting its significant potential in clinically automated EEG abnormality detection.

bioengineering↗

bioRxiv2024

Biological sex determines skeletal muscle atrophy in response to cortical TDP-43 pathology

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative condition. In ALS, wasting of skeletal muscle causes weakness, paralysis and ultimately, death due to respiratory failure. Diagnosis of ALS is a long process and delays in diagnosis are common, which impedes rapid provision of patient care and treatment. Additional tools or methodologies that improve early detection might help overcome the diagnostic delays and enhance survival and quality of life for people with ALS. In this study, we used a transgenic mouse model to create a detailed catalogue of skeletal muscle wasting with the goal of finding muscles that can be examined to enhance early diagnosis of ALS. MethodsCortical pathology was induced by crossing CaMKIIa-tTA and tetO-hTDP-43{Delta}NLS transgenic mice ({Delta}NLS). Transgenic expression was induced at 30-days postnatal via removal of doxycycline diet. Mice were aged to 15-, 20-, 30- and 45-days post transgene induction. Microdissection was applied to isolate 22 individual hindlimb muscles for measurement of weight. Both males and females were used at all timepoints. ResultsWe found that male and female {Delta}NLS mice exhibited hindlimb skeletal muscle atrophy relative to controls. Multiply innervated muscles, also known as series-fibered muscles, were especially vulnerable to atrophy. The strongest predictor of the atrophic response across all hindlimb muscles was the extent to which any individual muscle was larger in males than females, known also as sexual dimorphism. In males, muscles that are usually larger in males compared to females experienced the most atrophy. Conversely, in females, muscles that are usually of similar size between males and females experienced the most atrophy. Segregating muscles based on whether they were more affected in males or females revealed that hip extensors, knee flexors, knee extensors, ankle dorsiflexors and ankle evertors were more affected in males. Hip adductors, hip rotators, hip flexors and ankle plantarflexors were more affected in females. ConclusionsOur results demonstrate that the difference in the size of skeletal muscles in males compared to females is the most powerful predictor of muscle atrophy in response to dying forward pathology. This indicates that sex is a strong determinant of skeletal muscle vulnerability in ALS. Our results provide new insights into determinants of skeletal muscle atrophy and may help inform selection of muscles for diagnostic testing of ALS patients.

neuroscience↗

bioRxiv2024

Dynamic imaging of myelin pathology in physiologically preserved human brain tissue using third harmonic generation microscopy

Myelin pathology is known to play a central role in disorders such as multiple sclerosis (MS) among others. Despite this, the pathological mechanisms underlying these conditions are often difficult to unravel. Conventional techniques like immunohistochemistry or dye-based approaches, do not provide a temporal characterization of the pathophysiological aberrations responsible for myelin changes in human specimens. Here, to circumvent this curb, we present a label-free, live-cell imaging approach of myelin using recent advancements in nonlinear harmonic generation microscopy applied to physiologically viable human brain tissue from post-mortem donors. Gray and white matter brain tissue from epilepsy surgery and post-mortem donors was excised. To sustain viability of the specimens for several hours, they were subjected to either acute or organotypic slice culture protocols in artificial cerebral spinal fluid. Imaging was performed using a femtosecond pulsed 1060 nm laser to generate second harmonic generation (SHG) and third harmonic generation (THG) signals directly from myelin and axon-like structures without the need to add any labels. Experiments on acute human brain slices and post-mortem human slice cultures reveal that myelin, along with lipid bodies, are the prime sources of THG signal. We show that tissue viability is maintained over extended periods during THG microscopy, and that prolonged THG imaging is able to detect experimentally induced subtle alterations in myelin morphology. Finally, we provide practical evidence that live-cell imaging of myelin with THG microscopy is a sensitive tool to investigate subtle changes in white matter of neurological donors. Overall, our findings support that nonlinear live-cell imaging is a suitable setup for researching myelin morphology in neurological conditions like MS.

neuroscience↗

bioRxiv2024

Alzheimer's pathology disrupts flexible place cell coding and hippocampal-prefrontal neural dynamics during risky foraging decisions in mice

This study investigates how amyloid pathology influences hippocampal-prefrontal neural dynamics and decision-making in Alzheimers disease (AD) using 5XFAD mice, a well-established model system characterized by pronounced early amyloid pathology. Utilizing ecologically-relevant "approach food-avoid predator" foraging tasks, we observed that 5XFAD mice exhibited persistent risk-taking behaviors and reduced adaptability to changing threat conditions, indicative of impaired decision-making. Multi-regional neural recordings revealed rigid hippocampal CA1 place-cell fields, decreased sharp-wave ripple (SWR) frequencies, and disrupted medial prefrontal-hippocampal connectivity, all of which corresponded with deficits in behavioral flexibility during spatial risk scenarios. These findings highlight the critical role of SWR dynamics and corticolimbic circuit integrity in adaptive decision-making, with implications for understanding cognitive decline in AD in naturalistic contexts. By identifying specific neural disruptions underlying risky decision-making deficits, this work provides insights into the neural basis of cognitive dysfunction in AD and suggests potential targets for therapeutic intervention.

neuroscience↗

bioRxiv2024

TET2 contributes to gluconeogenesis and pathology of type 2 diabetes

The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4, contributing to the demethylation of FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4 on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.

cell biology↗

bioRxiv2024

Amyloid Beta Pathology Accelerates Alterations in the Visual Pathway of the 5xFAD Mouse

Alzheimers disease (AD) is a neurodegenerative disorder characterized by the formation of amyloid beta plaques and neurofibrillary tangles that leads to decreased quality of life due to behavioral, motor, and cognitive impairments. Due to the widespread pathological nature of AD, many brain regions are affected by amyloid beta plaques including regions important for vision such as the lateral geniculate nucleus (LGN) of the thalamus which is critical for relaying signals from the retina to the primary visual cortex. Using a wide range of techniques including electrophysiological approaches, in vivo and ex vivo imaging methods, and immunohistochemistry in a mouse model with progressing amyloidosis (5xFAD), the goal of this study was to determine whether AD-like pathology disrupts neuronal and synaptic structure and function in the visual system. In vivo electroretinogram recordings revealed photoreceptor dysfunction in the 6- and 9-month-old 5xFAD mice, while optical coherence tomography indicated no changes in retinal thickness. In the dorsolateral geniculate nucleus (dLGN), the rodent homolog of the primate LGN, we identified decreased densities of retinal ganglion cell axon terminals and fewer thalamocortical (TC) neuron cell bodies. No detectable deficits in excitatory synaptic function or TC neuron dendritic structure were seen in the dLGN, and reflexive visual behavior was also found to be normal in the 5xFAD mice. These results indicate relatively modest amyloid-triggered dysfunction in these stages of the visual system suggesting that amyloid beta plaque formation may play only a small role in the visual system dysfunction seen in AD patients. These results may also point to potential compensatory mechanisms that preserve function of visual pathways in the 5xFAD visual system.

neuroscience↗