Mouse Model Of Tauopathy Research Articles

High‐resolution non‐invasive whole brain imaging of tauopathy in a tauopathy mouse model

AbstractBackgroundAbnormal tauopathy accumulation play an important role in tauopathy diseases including Alzheimer’s disease and Frontotemporal dementia. There is a gap in high‐resolution non‐invasive imaging tool for detecting tauopathy deposits in animal models.MethodThe binding properties of a panel of imaging probes to 4‐repeat K18 tau fibril was assessed by using Thoflavin T assay and surface plasmon resonance assay. Next we established optimal dosage for tau probes in in vivo optoacoustic imaging, and developed transcranial whole brain imaging (130 micron spatial resolution) of tauopathy in P301L model of 4‐repeat tauopathy. T2 magnetic resonance imaging at 9.4T was performed for structural information and for volume‐of‐interest analysis of optoacoustic imaging data after co‐registration.ResultIn vitro assay showed binding to recombinant K18 tau fibril using PBB5, THK5351, but not T‐807 or MK‐6240. i.v. administration of PBB5 in P301L mice led to a retention of PBB5 in tau ladened cortex and hippocampus by registering with structural magnetic resonance imaging data. The specificity of PBB5 was validated by immunohistochemistry with anti‐phosphorylated tau antibody AT‐100.ConclusionOptoacoustic imaging with PBB5 facilitates preclinical high‐resolution whole brain imaging of tauopathy, for studying the spreading and accumulation of tauopathy, and for monitoring putative treatments targeting tau.

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation.

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.

Synaptic tau and synaptogyrin‐3 are promising targets to tackle tauopathies

Different pathogenic conditions (Alzheimer's disease and other tauopathies) induce detachment of Tau protein from microtubules. Detached Tau accumulates at synapses and binds to synaptic vesicle-associated protein Synaptogyrin-3, hampering vesicle mobility and neurotransmitter release (Zhou et al., Nature Communications 2017). Lowering the levels of Synaptogyrin-3 alleviates synaptic dysfunction in fruit flies and mouse primary neurons McInnes et al., Neuron 2018).We pursued two strategies to lower Synaptogyrin-3 expression in a tauopathy mouse model (human P301S Tau-expressing mice; "PS19 mouse line"). We generated a synaptogyrin-3 knockout mouse usign CRISPR/Cas9 and crossed it with Tau P301S mice. In paralel, we designed several antisense oligonucleotides (ASOs) against common sequences of mouse and human Synaptogyrin-3.We showed that lowering expression of Synaptogyrin-3 is benign in mice, but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. We screened several anti-Synaptogyrin-3 ASOs in vitro and selected the most effective one to further study its effects in vivo.Lowering Synaptogyrin-3 is safe and sufficient to prevent cognitive decline in Tau P301S mice. Further research will determine the therapeutic potential of interfering with the interaction of Tau and Synaptogyrin-3 in the context of tauopathies.

Testing the neuroinflammatory role of tau‐induced transposable elements in tauopathy

AbstractBackgroundNovel mechanisms through which pathogenic tau leads to neuronal toxicity remain largely unexplored as therapeutic targets for tauopathies. Activation of retrotransposons has been identified as a mechanism by which pathogenic tau contributes to neurotoxicity (Guo et al., 2018; Sun et al., 2018). To mobilize, retrotransposons are transcribed into RNA, reverse transcribed into DNA, and reinserted into the genome in a new location. Control of retrotransposons occurs at two levels, 1) transcriptional control via the location of retrotransposons within highly condensed heterochromatin and 2) by post‐transcriptional silencing mechanisms. While activated retrotransposons can create novel mutations via the “copy‐and‐paste” mechanism, double stranded RNAs (dsRNAs) formed from transposable element transcripts trigger the innate immune response, further contributing to cell toxicity (Cuellar et al., 2017; Kassiotis & Stoye, 2016; Roulois et al., 2015). Elevation of dsRNAs is documented in models of AGS and TDP‐43 proteinopathy, where dsRNA derived from repetitive elements can stimulate an interferon response (Ahmad et al., 2018; LaRocca, et al., 2019; Rodriguez et al., 2021).We are currently testing the hypothesis that transposable element‐derived dsRNAs stimulate the immune response in tauopathy.MethodBioinformatic analysis of bidirectional transcription was completed on RNA‐sequencing data from control and tau transgenic Drosophila. dsRNAs were quantified by J2 anti‐dsRNA antibody via immunofluorescence and ELISA. Analysis of inflammatory markers in Drosophila was completed by RNA‐sequencing and with a custom NanoString Gene Expression codeset.ResultWe find that dsRNAs are elevated in the brains of tau transgenic Drosophila, in the cortex of a mouse model of tauopathy, and in post‐mortem brain tissue from human tauopathy. Based on bioinformatic analysis, we identified retrotransposons that are bidirectionally transcribed in tau transgenic Drosophila. RNA sequencing and NanoString analysis of tau transgenic flies reveals elevated levels of innate immune response gene transcripts. Loss of transposon transcriptional silencing results in similar dsRNA production and immune system activation found in tau transgenic Drosophila.ConclusionOur goal is to determine if RNA intermediates from tau‐induced transposable elements are a therapeutic target for tauopathies. Overall, our findings support a model where dsRNA production induced by loss of transcriptional transposon silencing contributes to inflammation in tauopathy

Functional study in the young rTg4510 mouse model of tauopathy

AbstractBackgroundTau hyperphosphorylation (pTau) is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, pTau promotes neuroprotection by preventing seizure‐like activity.MethodTo further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (p30‐35), we studied the increase of pTau within the hippocampal area as well as hippocampal and locomotor function.ResultOur results showed that the very young rTg4510 model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from p30‐35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found an increased number of dendrites per cell in granule neurons.ConclusionAltogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology.

Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy

Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy

In vivo validation of therapeutic efficacy of a small molecule lead targeting tau self‐association in JNPL3 mice

AbstractBackgroundSmall molecules were screened and optimized for inhibiting tau self‐association, the initial step in the formation of soluble toxic tau oligomers and larger insoluble aggregates. This approach is differentiated from other tau aggregation inhibitor programs that have largely focused on inhibiting formation and/or dissociating large and relatively inert fibrils which could generate toxic tau oligomer seeds. Small molecules inhibitors are agnostic to specific post‐translational modifications, conformational changes or strains of tau aggregates, and have superior access to their target in the CNS relative to immunotherapeutic approaches. We have previously shown in vivo efficacy of a lead compound in preventive studies in htau (Davidowitz et al., 2020) and human tau P301L JNPL3 mouse models of tauopathy. The tau P301L mutation is the most common FTDP‐17 mutation and causes tau aggregation and motor deficits with age (Lewis et al., 2000).MethodBlinded studies of homozygous female tau 4R/0N P301L JNPL3 mice were performed at an independent laboratory where mice were treated for five months by administration of our lead compound in feed from 7 to 12 months‐of‐age. The four groups of mice in the study were baseline (7 months; n=20), vehicle, and two treatment groups (40 and 80 mg/kg doses; n=25 each). To quantify levels of Sarkosyl‐insoluble tau, self‐associated tau, and phosphorylated tau in the treated and control groups of mice ELISAs were performed (Acker et al., 2012; Forest et al., 2019). Rotarod and open field studies were performed to evaluate motor behavior.ResultEfficacy was shown in the cortex of treated mice that had reduced levels of self‐associated tau below baseline, baseline levels of insoluble tau aggregates, and reduced levels of aberrantly phosphorylated tau with statistical significance. In the hindbrain there was reduction of insoluble tau aggregates in the 40 mg/kg group compared to vehicle. Treatment groups showed improved Rotarod performance compared to baseline and vehicle groups.ConclusionTreatment with the lead compound reduced tau aggregation and improved motor behavior in aged JNPL3 mice and support preclinical development of the lead for clinical studies.

Heparan sulfate: In vitro and in vivo proof of efficacy of this new therapeutic strategy for halting Alzheimer disease‐related tauopathy development

AbstractBackgroundDeposition of amyloid plaques and neurofibrillary tangles composed of abnormally phosphorylated tau are the neuropathological hallmarks of Alzheimer's disease (AD). However, years before the accumulation of protein aggregates, the abnormal intraneuronal accumulation of heparan sulfates (HS) is observed. This phenomenon breaks a dogma, since HS are classically located on the cell surface and in the extracellular matrix, leading to a new cell autonomous concept in tauopathy, which is the conceptual core of the FET‐OPEN ArrestAD 737390 project. Previously, we provide evidence that inside the cell, HS act as molecular chaperones inducing in Tau conformational changes favoring its abnormal phosphorylation and aggregation (Sepulveda‐Diaz JE. Brain 2015, 138(Pt 5):1339‐54). Thus, molecules able to act on heparan sulfate pathway could represent a new class of compounds for the treatment of AD‐related tauopathies.MethodPAPS is the universal sulfate donor involved in HS biosynthesis and structurally related to ATP. Thus, we first screened kinase inhibitor libraries in a sulfotransferase enzymatic assay (Byrne et al., Biochem. J. 2018; 475:2417‐2433). This strategy, in addition to a HS mimetic, were evaluated for their ability to prevent tauopathy in cells. The best molecules were then evaluated in two transgenic mice model of AD. Thereafter, proof‐of‐concept of the efficacy of compounds selected with this strategy, as well as HS mimetic (Barritault D. Glycoconj J. 2017; 34(3):325‐338) for halting AD‐related tauopathies development was assessed first in vitro and then in vivo.ResultsThe screening of libraries allowed the identification of 3 hit compounds that, in addition to a HS mimetic, were evaluated for their ability to prevent tauopathy in cells. Two molecules, one HSSTs inhibitor and one heparan sulfate mimetic, were able to reduce tauopathy in cells and in 3xTg‐AD and rTg4510 mouse models of tauopathy. In the in vivo assessment in males and females 3xTg‐AD, the behavioral dose‐response of these molecules on the cognitive, neuropsychiatric‐like and motor AD‐phenotypes was determined.ConclusionOur results support the FET‐OPEN RIA ArrestAD cell autonomous hypothesis of tauopathy based in altered heparan sulfate biology and place HS and their biosynthetic enzymes as a potential therapeutic target for AD.

The Alzheimer's disease risk gene CD2AP modulates mammalian synaptic structure and plasticity

CD2-Associated protein (CD2AP) is associated with increased risk of late-onset Alzheimer's disease. We have previously shown that loss of CD2AP's Drosophila homolog, cindr, exacerbates Tau toxicity and impairs synaptic maturation and function at the neuromuscular junction. However, little is understood about CD2AP at the central mammalian synapse. The present study demonstrates conservation of CD2AP function at the pre-synapse from fly to mouse, as well as characterizes CD2AP's role in maintaining post-synaptic structure and function.We examine short- and long-term plasticity using electrophysiologic measurements and synaptic structure and morphology using confocal imaging. Experiments were performed on homozygous CD2AP knockout mice and heterozygous CD2AP knockout mice to investigate potential haploinsufficient requirement. Mice constitutively expressing Cas9 endonuclease were used for brain-specific CD2AP knockout.Homozygous and heterozygous CD2AP knockout mice exhibit increased paired-pulse facilitation, a form of short-term plasticity. This matches data from Drosophila, implying conservation from fly to mouse, and indicates decreased probability of presynaptic vesicle release with CD2AP loss. We found no change in long-term potentiation (LTP) at 4 to 6 weeks; however, our preliminary experiments demonstrate decreased LTP in aged heterozygous CD2AP knockouts. Ongoing experiments are investigating age as a factor in CD2AP function. Lastly, CD2AP knockout neurons exhibit increased dendritic branching and homozygous knockout mice have increased expression of postsynaptic density protein 95.Our analyses implicate CD2AP in modulation of synaptic plasticity and structure, suggest a conservation of CD2AP function from flies to mice, and support CD2AP haploinsufficiency. Going forward, we will investigate how CD2AP loss affects existing Alzheimer's pathogenesis in a P301S tauopathy mouse model.

Arterial spin labeling demonstrates preserved regional cerebral blood flow in the P301L mouse model of tauopathy

There is growing evidence for the vascular contribution to cognitive impairment and dementia in Alzheimer’s disease (AD) and other neurodegenerative diseases. While perfusion deficits have been observed in patients with Alzheimer’s disease and tauopaties, little is known about the role of tau in vascular dysfunction. In the present study, regional cerebral blood (rCBF) was characterized in P301L mice with arterial spin labeling. No differences in rCBF in P301L mice compared to their age-matched non-transgenic littermates at mid (10–12 months of age) and advanced (19–21 months of age) disease stages. This was concomitant with preservation of cortical brain structure as assessed with structural T2-weighted magnetic resonance imaging. These results show that hypoperfusion and neurodegeneration are not a phenotype of P301L mice. More studies are thus needed to understand the relationship of tau, neurodegeneration and vascular dysfunction and its modulators in AD and primary tauopathies.

MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration.

Recent increases in human longevity have been accompanied by a rise in the incidence of dementia, highlighting the need to preserve cognitive function in an aging population. A small percentage of individuals with pathological hallmarks of neurodegenerative disease are able to maintain normal cognition. Although the molecular mechanisms that govern this neuroprotection remain unknown, individuals that exhibit cognitive resilience (CgR) represent a unique source of therapeutic insight. For both humans and animal models, living in an enriched, cognitively stimulating environment is the most effective known inducer of CgR. To understand potential drivers of this phenomenon, we began by profiling the molecular changes that arise from environmental enrichment in mice, which led to the identification of MEF2 transcription factors (TFs). We next turned to repositories of human clinical and brain transcriptomic data, where we found that the MEF2 transcriptional network was overrepresented among genes that are most predictive of end-stage cognition. Through single-nucleus RNA sequencing of cortical tissue from resilient and nonresilient individuals, we further confirmed up-regulation of MEF2C in resilient individuals to a subpopulation of excitatory neurons. Last, to determine the causal impact of MEF2 on cognition in the context of neurodegeneration, we overexpressed Mef2a/c in the PS19 mouse model of tauopathy and found that this was sufficient to improve cognitive flexibility and reduce hyperexcitability. Overall, our findings reveal a previously unappreciated role for MEF2 TFs in promoting CgR, highlighting their potential as biomarkers or therapeutic targets for neurodegeneration and healthy aging.

P2X7-deficiency improves plasticity and cognitive abilities in a mouse model of Tauopathy.

Alzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid β (Aβ) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in Aβ-mediated neurodegeneration but the relationship between P2X7 and Tau remained overlooked. Such a link was supported by cortical upregulation of P2X7 in patients with various type of frontotemporal lobar degeneration, including mutation in the Tau-coding gene, MAPT, as well as in the brain of a Tauopathy mouse model (THY-Tau22). Subsequent phenotype analysis of P2X7-deficient Tau mice revealed the instrumental impact of this purinergic receptor. Indeed, while P2X7-deficiency had a moderate effect on Tau pathology itself, we observed a significant reduction of microglia activation and of Tau-related inflammatory mediators, particularly CCL4. Importantly, P2X7 deletion ultimately rescued synaptic plasticity and memory impairments of Tau mice. Altogether, the present data support a contributory role of P2X7 dysregulation on processes governing Tau-induced brain anomalies. Due to the convergent role of P2X7 blockade in both Aβ and Tau background, P2X7 inhibitors might prove to be ideal candidate drugs to curb the devastating cognitive decline in Alzheimer's disease and Tauopathies.

Age-related cognitive decline in spatial learning and memory of C57BL/6J mice

During the last decades, most of the preclinical neurodegenerative research was performed in mouse models of amyloidosis, tauopathies or α-synucleinopathies preferentially maintained on a C57BL/6J background. However, comprehensive neurobehavioural data from C57BL/6J mice outlining the critical point of spontaneous cognitive decline are incomplete. In this study, we aimed for the neurobehavioural phenotyping of hippocampus-dependent spatial learning and memory of aging C57BL/6J mice. Neurobehavioural phenotyping was performed by means of a Morris Water Maze (MWM) and a Novel Object Recognition (NOR) test. MWM measurements revealed signs of age-related memory loss in C57BL/6J animals from the age of 6 months onward. The NOR assessment strengthened latter finding by decreasing discrimination indexes (DI) and recognition indexes (RI) starting from the age of 6 months. Taken together, these findings contribute to the current knowledge of spontaneous cognitive behaviours of this perhaps most widely used mouse strain and serve as a benchmark for dementia mouse models to distinguish spontaneous from pathological neurodegenerative behaviour.

Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy.

Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. We constructed adeno-associated virus carrying hTau cDNA (AAVhTau) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology.

Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model.

Protein malnutrition is epidemiologically suggested as a potential risk factor for senile dementia, although molecular mechanisms linking dietary proteins and amino acids to neurodegeneration remain unknown. Here, we show that a low-protein diet resulted in down-regulated expression of synaptic components and a modest acceleration of brain atrophy in mice modeling neurodegenerative tauopathies. Notably, these abnormal phenotypes were robustly rescued by the administration of seven selected essential amino acids. The up-regulation of inflammation-associated gene expression and progressive brain atrophy in the tauopathy model were profoundly suppressed by treatment with these essential amino acids without modifications of tau depositions. Moreover, the levels of kynurenine, an initiator of a pathway inducing neuroinflammatory gliosis and neurotoxicity in the brain, were lowered by treatment through inhibition of kynurenine uptake in the brain. Our findings highlight the importance of specific amino acids as systemic mediators of brain homeostasis against neurodegenerative processes.

Increased Signal Delays and Unaltered Synaptic Input Pattern Recognition in Layer III Neocortical Pyramidal Neurons of the rTg4510 Mouse Model of Tauopathy: A Computer Simulation Study With Passive Membrane.

Abnormal tau proteins are involved in pathology of many neurodegenerative disorders. Transgenic rTg4510 mice express high levels of human tau protein with P301L mutation linked to chromosome 17 that has been associated with frontotemporal dementia with parkinsonism. By 9 months of age, these mice recapitulate key features of human tauopathies, including presence of hyperphosphorylated tau and neurofibrillary tangles (NFTs) in brain tissue, atrophy and loss of neurons and synapses, and hyperexcitability of neurons, as well as cognitive deficiencies. We investigated effects of such human mutant tau protein on neuronal membrane, subthreshold dendritic signaling, and synaptic input pattern recognition/discrimination in layer III frontal transgenic (TG) pyramidal neurons of 9-month-old rTg4510 mice and compared these characteristics to those of wild-type (WT) pyramidal neurons from age-matched control mice. Passive segmental cable models of WT and TG neurons were set up in the NEURON simulator by using three-dimensionally reconstructed morphology and electrophysiological data of these cells. Our computer simulations predict leakage resistance and capacitance of neuronal membrane to be unaffected by the mutant tau protein. Computer models of TG neurons showed only modest alterations in distance dependence of somatopetal voltage and current transfers along dendrites and in rise times and half-widths of somatic Excitatory Postsynaptic Potential (EPSPs) relative to WT control. In contrast, a consistent and statistically significant slowdown was detected in the speed of simulated subthreshold dendritic signal propagation in all regions of the dendritic surface of mutant neurons. Predictors of synaptic input pattern recognition/discrimination remained unaltered in model TG neurons. This suggests that tau pathology is primarily associated with failures/loss in synaptic connections rather than with altered intraneuronal synaptic integration in neurons of affected networks.

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model.

Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD‐like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone‐lysine N‐methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5–7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.

Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy

Pathological aggregation of tau and neuroinflammatory changes mark the clinical course of Alzheimer's disease and related tauopathies. To understand the correlation between these pathological hallmarks and functional deficits, we assessed behavioral and physiological deficits in the PS19 mouse model, a broadly utilized model of tauopathy. At 9 months, PS19 mice have characteristic hyperactive behavior, a decline in motor strength, and deterioration in physiological conditions marked by lower body temperature, reduced body weight, and an increase in measures of frailty. Correlation of these deficits with different pathological hallmarks revealed that pathological tau species, characterized by soluble p-tau species, and tau seeding bioactivity correlated with impairment in grip strength and thermal regulation. On the other hand, astrocyte reactivity showed a positive correlation with the hyperactive behavior of the PS19 mice. These results suggest that a diverse spectrum of soluble pathological tau species could be responsible for different symptoms and that neuroinflammation could contribute to functional deficits independently from tau pathology. These observations enhance the necessity of a multi-targeted approach for the treatment of neurodegenerative tauopathies.

Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction.

Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.

Impact of Sterilization Methods on the Seeding Ability of Human Tau Proteopathic Seeds.

The protein tau, when misfolded in neurodegenerative diseases, has several prion-like properties including being able to spread by cell-to-cell transfer, induce templated seeding, and exist in distinct conformational strains. These properties of transmission may present health hazards when lesion-containing biospecimens are used in research and neuropathology laboratories. We evaluated the impact standard sterilization and cleaning methods have on the capacity of tau seeds to induce aggregation. We employed a previously developed, highly sensitive FRET-based biosensor assay to assess remnant tau seeding after exposure to these procedures. For tau species derived from human Alzheimer disease tissue (brain homogenate and sarkosyl-insoluble fibrils), both autoclaving and incubation in 90.6% formic acid were sufficient to reduce tau bioactivity. By contrast, boiling was not always effective in completely blocking bioactivity in the seeding assay. Notably, only formic acid incubation was able to produce a similar reduction in tissue from a P301L mutant tau mouse model of tauopathy. Our study highlights nuances in methods for inactivation of tau seeding which may support adapted tissue processing procedures, especially in research settings. These findings also highlight the importance of universal precautions when handling human neuropathological and research laboratory materials.