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1.
Aging Brain ; 5: 100110, 2024.
Article in English | MEDLINE | ID: mdl-38419621

ABSTRACT

Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.

2.
bioRxiv ; 2024 Jan 26.
Article in English | MEDLINE | ID: mdl-38328104

ABSTRACT

Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific signs and vulnerabilities. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following repetitive mild traumatic brain injuries (rmTBIs). In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and Neurite Orientation Dispersion and Density Imaging (NODDI). Utilizing the CHIMERA model, we conducted rmTBIs or sham (control) procedures on young (2.5-3 months old) and aged (22-month-old) male and female mice to model high risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposing effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean, radial, axial diffusivity, fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Inflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in aged animals. These findings provide a comprehensive understanding of the intricate interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBIs.

3.
bioRxiv ; 2023 Nov 17.
Article in English | MEDLINE | ID: mdl-38014109

ABSTRACT

Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.

4.
bioRxiv ; 2023 Jul 25.
Article in English | MEDLINE | ID: mdl-37546843

ABSTRACT

Metabolites, lipids, and glycans are fundamental biomolecules involved in complex biological systems. They are metabolically channeled through a myriad of pathways and molecular processes that define the physiology and pathology of an organism. Here, we present a blueprint for the simultaneous analysis of spatial metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. Complimenting an original experimental protocol, our workflow includes a computational framework called Spatial Augmented Multiomics Interface (Sami) that offers multiomics integration, high dimensionality clustering, spatial anatomical mapping with matched multiomics features, and metabolic pathway enrichment to providing unprecedented insights into the spatial distribution and interaction of these biomolecules in mammalian tissue biology.

5.
Eur Heart J ; 44(17): 1560-1570, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37122097

ABSTRACT

BACKGROUND: Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer's disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies 'beyond the brain'. This study aims to establish tau's putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). METHODS AND RESULTS: A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. CONCLUSION: The study presents new mechanistic evidence and potential treatment for the brain-heart tauopathy axis in myocardial and brain degenerative diseases and ageing.


Subject(s)
Alzheimer Disease , Tauopathies , Humans , Mice , Animals , tau Proteins/chemistry , tau Proteins/genetics , tau Proteins/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Tauopathies/metabolism , Tauopathies/pathology , Microtubules/metabolism , Microtubules/pathology , Myocardium/pathology
6.
J Neurotrauma ; 40(19-20): 2037-2049, 2023 10.
Article in English | MEDLINE | ID: mdl-37051703

ABSTRACT

Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps of the molecular mechanisms responsible for neurodegeneration. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. Using the Closed-Head Impact Model of Engineered Rotational Acceleration, or CHIMERA, we measured neural changes following injury, including brain volume, diffusion tensor imaging, and resting-state functional magnetic resonance imaging coupled with graph theory and functional connectivity analyses. We determined the effect of rmTBI on markers of gliosis and used NanoString-GeoMx to add a digital-spatial protein profiling analysis of neurodegenerative disease-associated proteins in gray and white matter regions. Our analyses revealed aberrant connectivity changes in the thalamus, independent of microstructural damage or neuroinflammation. We also identified distinct changes in the levels of proteins linked to various neurodegenerative processes including total and phospho-tau species and cell proliferation markers. Together, our data show that rmTBI significantly alters brain functional connectivity and causes distinct protein changes in morphologically intact brain areas.


Subject(s)
Brain Concussion , Brain Injuries, Traumatic , Neurodegenerative Diseases , Humans , Brain Concussion/complications , Neurodegenerative Diseases/pathology , Diffusion Tensor Imaging , Brain/pathology , Brain Injuries, Traumatic/complications , Magnetic Resonance Imaging
7.
Behav Brain Res ; 437: 114106, 2023 02 02.
Article in English | MEDLINE | ID: mdl-36089100

ABSTRACT

Approximately 60-70 million people suffer from traumatic brain injury (TBI) each year. Animal models continue to be paramount in understanding mechanisms of cellular dysfunction and testing new treatments for TBI. Enhancing the translational potential of novel interventions therefore necessitates testing pre-clinical intervention strategies with clinically relevant cognitive assays. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based Paired Associates Learning (PAL) task, which is part of the Cambridge Neuropsychological Test Automated Battery. In humans, the PAL task has been used to assess cognitive deficits in the ability to form stimulus-location associations in a multitude of disease states, including TBI. Although the use of PAL in animal models could be important for understanding the clinical severity of cognitive impairment post-injury and throughout intervention, to date, the extent to which a rat model of TBI produces deficits in PAL task performance has not yet been reported. This study details the behavioral consequences of the CCI injury model with a Trial-by-Trial analysis of PAL performance that enables behavioral strategy use to be inferred. Following behavior, the extent of the injury was quantified with histology and staining for the presence of glial fibrillary acid protein and ionized calcium-binding adapter molecule 1. Rats that received unilateral CCI were impaired on the PAL task and showed more aberrant response-driven behavior. The magnitude of PAL impairment was also correlated with Iba1 staining in the thalamus. These observations suggest that PAL could be useful for pre-clinical assessments of novel interventions for treating TBI.


Subject(s)
Brain Injuries, Traumatic , Cognition Disorders , Animals , Rats , Brain Injuries, Traumatic/complications , Cognition Disorders/pathology , Disease Models, Animal , Neuropsychological Tests , Paired-Associate Learning , Parietal Lobe/pathology
8.
Acta Neuropathol Commun ; 10(1): 13, 2022 01 31.
Article in English | MEDLINE | ID: mdl-35101132

ABSTRACT

BACKGROUND: The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain controversial. Some studies suggest that moderate to severe TBI is sufficient to promote tau pathology; however, others suggest that it is simply a consequence of aging. We therefore conducted a systematic narrative review of the literature addressing whether a single moderate to severe head injury leads to long-term development of tauopathy in both humans and animal models. METHODS: Studies considered for inclusion in this review assessed a single moderate to severe TBI, assessed tau pathology at long-term timepoints post-injury, comprised experimental or observational studies, and were peer-reviewed and published in English. Databases searched included: PUBMED, NCBI-PMC, EMBASE, Web of Science, Academic Search Premiere, and APA Psychnet. Search results were uploaded to Covidence®, duplicates were removed, and articles underwent an abstract and full-text screening process. Data were then extracted and articles assessed for risk of bias. FINDINGS: Of 4,150 studies screened, 26 were eligible for inclusion, of which 17 were human studies, 8 were preclinical animal studies, and 1 included both human and preclinical animal studies. Most studies had low to moderate risk of bias. Most human and animal studies (n = 12 and 9, respectively) suggested that a single moderate to severe TBI resulted in greater development of long-term tauopathy compared to no history of head injury. This conclusion should be interpreted with caution, however, due to several limitations: small sample sizes; inconsistencies in controlling for confounding factors that may have affected tau pathology (e.g., family history of dementia or neurological illnesses, apolipoprotein E genotype, etc.), inclusion of mostly males, and variation in reporting injury parameters. INTERPRETATION: Results indicate that a single moderate to severe TBI leads to greater chronic development of tauopathy compared to no history of head injury. This implies that tau pathology induced may not be transient, but can progressively develop over time in both humans and animal models. Targeting these tau changes for therapeutic intervention should be further explored to elucidate if disease progression can be reversed or mitigated.


Subject(s)
Brain Injuries, Traumatic/complications , Brain/pathology , Tauopathies/etiology , Animals , Brain Injuries, Traumatic/pathology , Disease Models, Animal , Humans , Tauopathies/pathology
9.
Mol Cell ; 81(20): 4209-4227.e12, 2021 10 21.
Article in English | MEDLINE | ID: mdl-34453888

ABSTRACT

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.


Subject(s)
Adenosine/analogs & derivatives , Alzheimer Disease/metabolism , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism , RNA Processing, Post-Transcriptional , RNA/metabolism , tau Proteins/metabolism , Adenosine/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Case-Control Studies , Disease Models, Animal , Disease Progression , Female , HEK293 Cells , Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics , Humans , Male , Methylation , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Protein Aggregates , Protein Aggregation, Pathological , RNA/genetics , Severity of Illness Index , tau Proteins/genetics
10.
Aging Cell ; 20(7): e13416, 2021 07.
Article in English | MEDLINE | ID: mdl-34117818

ABSTRACT

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3-4 months old) infused with oligomeric Aß peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aß plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.


Subject(s)
Alzheimer Disease/genetics , NFATC Transcription Factors/antagonists & inhibitors , Plaque, Amyloid/physiopathology , Animals , Disease Models, Animal , Mice
11.
Exp Neurol ; 343: 113766, 2021 09.
Article in English | MEDLINE | ID: mdl-34029610

ABSTRACT

Tauopathies, including Alzheimer's disease, are characterized by progressive accumulation of hyperphosphorylated and pathologic tau protein in association with onset of cognitive and behavioral impairment. Tau pathology is also associated with increased susceptibility to seizures and epilepsy, with tau-/- mice showing seizure resistance in some epilepsy models. To better understand how tau pathology is related to neuronal excitability, we performed whole-cell patch-clamp electrophysiology in dentate gyrus granule cells of tau-/- and human-tau expressing, htau mice. The htau mouse is unique from other transgenic tau models in that the endogenous murine tau gene has been and replaced with readily phosphorylated human tau. We assessed several measures of neuronal excitability, including evoked action potential frequency and excitatory synaptic responses in dentate granule cells from tau-/-, htau, and non-transgenic control mice at 1.5, 4, and 9 months of age. Compared to age matched controls, dentate granule cells from both tau-/- and htau mice had a lower peak frequency of evoked action potentials and greater paired pulse facilitation, suggesting reduced neuronal excitability. Our results suggest that neuronal excitability is more strongly influenced by the absence of functional tau than by the presence of pathologic tau. These results also suggest that tau's effect on neuronal excitability is more complex than previously understood.


Subject(s)
Dentate Gyrus/cytology , Dentate Gyrus/metabolism , Excitatory Postsynaptic Potentials/physiology , tau Proteins/biosynthesis , Age Factors , Animals , Female , Gene Expression , Humans , Male , Membrane Potentials/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Organ Culture Techniques , tau Proteins/genetics
12.
Transl Psychiatry ; 11(1): 251, 2021 04 28.
Article in English | MEDLINE | ID: mdl-33911072

ABSTRACT

Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Amyloid beta-Peptides/metabolism , Animals , Hippocampus/diagnostic imaging , Hippocampus/metabolism , Humans , Interleukin-6 , Mice , Plaque, Amyloid
13.
Int J Mol Sci ; 22(3)2021 Jan 26.
Article in English | MEDLINE | ID: mdl-33530349

ABSTRACT

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer's disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.


Subject(s)
Neurons/drug effects , Neurons/metabolism , Protein Kinase Inhibitors/pharmacology , Tauopathies/etiology , Tauopathies/metabolism , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Humans , Mice , Mice, Transgenic , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/metabolism , Phosphorylation , Protein Kinase Inhibitors/therapeutic use , Proteome , Proteomics/methods , Severity of Illness Index , Tauopathies/diagnosis , Tauopathies/drug therapy , Unfolded Protein Response , eIF-2 Kinase/metabolism , tau Proteins/metabolism
14.
Prog Neurobiol ; 196: 101892, 2021 01.
Article in English | MEDLINE | ID: mdl-32795489

ABSTRACT

A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor. In contrast, PERK prolonged activation leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), in which aging confers a high risk of Alzheimer disease (AD). By investigating human DS frontal cortices, we found early and sustained PERK activation associated with the induction of eIF2α and ATF4 downstream signals. We also observed that the Nrf2 response is uncoupled from PERK and its antioxidant effects are repressed in a mechanism implicating the transcription repressor Bach1. The pharmacological inhibition of PERK in DS mice reduced eIF2α-related translational repression and promoted Nrf2 nuclear translocation, favoring the rescue of Nrf2/Bach1 imbalance. The further analysis of peripheral cells from living DS individuals provided strong support of the pathological link between PERK and trisomy 21. Our results suggest that failure to regulate the PERK pathway is a peculiar characteristic of DS pathology and it may represent an essential step to promote cellular dysfunction, which actively contributes in the brain to the early development of AD.


Subject(s)
Alzheimer Disease/metabolism , Down Syndrome/metabolism , Protein Kinase Inhibitors/pharmacology , Unfolded Protein Response/physiology , eIF-2 Kinase/antagonists & inhibitors , eIF-2 Kinase/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Autopsy , Basic-Leucine Zipper Transcription Factors/metabolism , Child , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , NF-E2-Related Factor 2/metabolism , Young Adult
15.
Neurobiol Dis ; 141: 104939, 2020 07.
Article in English | MEDLINE | ID: mdl-32413399

ABSTRACT

Frontotemporal dementias (FTDs) encompass several disorders commonly characterized by progressive frontotemporal lobar degeneration and dementia. Pathologically, TDP-43, FUS, dipeptide repeats, and tau constitute the protein aggregates in FTD, which in turn coincide with heterogeneity in clinical variants. The underlying molecular etiology explaining the formation of each type of protein aggregate remains unclear; however, dysregulated RNA metabolism rises as a common pathogenic factor. Alongside with TDP-43 and FUS, which bind to and regulate RNA dynamics, emerging data suggest that tau may also regulate RNA metabolism and translation. The complex mechanisms that drive translational selectivity in turn regulate the broad clinical presentation of FTDs. Here, we focus on the enigmatic relationship between tau and RNA and review the mechanisms of tau-mediated dysregulation of RNA in tauopathies such as FTD.


Subject(s)
Brain/metabolism , Frontotemporal Dementia/metabolism , RNA/metabolism , Tauopathies/metabolism , tau Proteins/metabolism , Animals , Brain/pathology , Frontotemporal Dementia/pathology , Humans , Protein Aggregation, Pathological/metabolism , Tauopathies/pathology
16.
Exp Neurol ; 326: 113180, 2020 04.
Article in English | MEDLINE | ID: mdl-31930992

ABSTRACT

In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.


Subject(s)
Cognition Disorders/etiology , Cognition Disorders/psychology , Head Injuries, Closed/complications , Head Injuries, Closed/psychology , Tauopathies/complications , Tauopathies/psychology , Animals , Mice , Mice, Neurologic Mutants
17.
Int J Mol Sci ; 20(14)2019 Jul 18.
Article in English | MEDLINE | ID: mdl-31323794

ABSTRACT

Impairments in translation have been increasingly implicated in the pathogenesis and progression of multiple neurodegenerative diseases. Assessing the spatiotemporal dynamics of translation in the context of disease is a major challenge. Recent developments in proteomic analyses have enabled the resolution of nascent peptides in a short timescale on the order of minutes. In addition, a quantitative analysis of translation has progressed in vivo, showing remarkable potential for coupling these techniques with cognitive and behavioral outcomes. Here, we review these modern approaches to measure changes in translation and ribosomal function with a specific focus on current applications in the mammalian brain and in the study of neurodegenerative diseases.


Subject(s)
Proteomics/methods , Ribosomes/metabolism , Animals , Humans , Neurodegenerative Diseases/metabolism , Protein Biosynthesis/physiology
18.
Acta Neuropathol ; 137(4): 571-583, 2019 04.
Article in English | MEDLINE | ID: mdl-30759285

ABSTRACT

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer's disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.


Subject(s)
Brain/metabolism , Protein Biosynthesis/physiology , Ribosomal Proteins/metabolism , Ribosomes/metabolism , Transcriptome , tau Proteins/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Brain/pathology , Humans , Mice , Mice, Transgenic , Ribosomal Proteins/genetics , Tauopathies/genetics , Tauopathies/metabolism , Tauopathies/pathology , tau Proteins/genetics
19.
Nat Med ; 25(1): 165-175, 2019 01.
Article in English | MEDLINE | ID: mdl-30617325

ABSTRACT

Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Fibronectins/metabolism , Memory Disorders/complications , Memory Disorders/physiopathology , Neuronal Plasticity , Physical Conditioning, Animal , Adolescent , Adult , Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/genetics , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Down-Regulation , Female , Fibronectins/cerebrospinal fluid , Fibronectins/genetics , Humans , Long-Term Potentiation , Male , Mice, Inbred C57BL , Middle Aged , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , RNA, Messenger/genetics , RNA, Messenger/metabolism , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Signal Transduction
20.
Neurobiol Aging ; 72: 188.e3-188.e12, 2018 12.
Article in English | MEDLINE | ID: mdl-30201328

ABSTRACT

Systematic epistasis analyses in multifactorial disorders are an important step to better characterize complex genetic risk structures. We conducted a hypothesis-free sex-stratified genome-wide screening for epistasis contributing to Alzheimer's disease (AD) susceptibility. We identified a statistical epistasis signal between the single nucleotide polymorphisms rs3733980 and rs7175766 that was associated with AD in males (genome-wide significant pBonferroni-corrected=0.0165). This signal pointed toward the genes WW and C2 domain containing 1, aka KIBRA; 5q34 and TLN2 (talin 2; 15q22.2). Gene-based meta-analysis in 3 independent consortium data sets confirmed the identified interaction: the most significant (pmeta-Bonferroni-corrected=9.02*10-3) was for the single nucleotide polymorphism pair rs1477307 and rs4077746. In functional studies, WW and C2 domain containing 1, aka KIBRA and TLN2 coexpressed in the temporal cortex brain tissue of AD subjects (ß=0.17, 95% CI 0.04 to 0.30, p=0.01); modulated Tau toxicity in Drosophila eye experiments; colocalized in brain tissue cells, N2a neuroblastoma, and HeLa cell lines; and coimmunoprecipitated both in brain tissue and HEK293 cells. Our finding points toward new AD-related pathways and provides clues toward novel medical targets for the cure of AD.


Subject(s)
Alzheimer Disease/genetics , Epistasis, Genetic/genetics , Intracellular Signaling Peptides and Proteins/genetics , Phosphoproteins/genetics , Sex Characteristics , Talin/genetics , Cohort Studies , Female , Humans , Male , Meta-Analysis as Topic , Sex Factors
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