Sodium channel inhibitors alter the progress of tangle development in a mouse model of dementia

Sodium channel inhibitors alter the progress of tangle development in a mouse model of dementia | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Sodium channel inhibitors alter the progress of tangle development in a mouse model of dementia View ORCID Profile Chloe M. Hall , Martha Roberts , Roshni A. Desai , View ORCID Profile Damian M. Cummings , Jamie Bilsland , View ORCID Profile Paul Whiting , Kenneth J. Smith , View ORCID Profile Frances A Edwards doi: https://doi.org/10.1101/2024.08.26.609302 Chloe M. Hall 1 Department of Neuroscience, Physiology and Pharmacology, University College London , Gower St, London WC1E 6BT Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Chloe M. Hall Martha Roberts 1 Department of Neuroscience, Physiology and Pharmacology, University College London , Gower St, London WC1E 6BT Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roshni A. Desai 2 Department of Neuroinflammation, UCL Queen Square Institute of Neurology , 1 Wakefield Street, London, WC1N 1PJ Find this author on Google Scholar Find this author on PubMed Search for this author on this site Damian M. Cummings 1 Department of Neuroscience, Physiology and Pharmacology, University College London , Gower St, London WC1E 6BT Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Damian M. Cummings Jamie Bilsland 3 Alzheimer’s Research UK UCL Drug Discovery Institute, Faculty of Brain Sciences, University College London , The Cruciform Building, Gower Street, London WC1E 6BT Find this author on Google Scholar Find this author on PubMed Search for this author on this site Paul Whiting 3 Alzheimer’s Research UK UCL Drug Discovery Institute, Faculty of Brain Sciences, University College London , The Cruciform Building, Gower Street, London WC1E 6BT Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Paul Whiting Kenneth J. Smith 2 Department of Neuroinflammation, UCL Queen Square Institute of Neurology , 1 Wakefield Street, London, WC1N 1PJ Find this author on Google Scholar Find this author on PubMed Search for this author on this site Frances A Edwards 1 Department of Neuroscience, Physiology and Pharmacology, University College London , Gower St, London WC1E 6BT Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Frances A Edwards For correspondence: f.a.edwards{at}ucl.ac.uk Abstract Full Text Info/History Metrics Preview PDF ABSTRACT Sodium channel inhibitors have been reported to protect against a range of neuroinflammatory and neurodegenerative diseases. Here the effect of chronic administration of two Na + channel inhibitors with different mechanisms of action, phenytoin and GS967 are tested in mouse models of different stages of Alzheimer’s disease. Subtle changes in the distribution of plaque sizes were observed in App NLGF/NLGF mouse at 3 months of age, after being fed control or drug-supplemented chow from weaning onwards, with phenytoin treatment resulting in a significant increase in the frequency of the smallest plaques and a decrease in large plaques. The later pathology of neurofibrillary tangles was studied, in old age, by supplementing the food of transgenic mice with a P301L mutation in Tau. Chronic administration of Na + inhibitors from 15 months of age resulted in a decrease in the density of MC1-positive neurofibrillary tangles, possibly due to effects on microglial Na + channels. The density of microglial cells was strongly correlated with the density of neurofibrillary tangles but only in mice treated with the Na + inhibitors. INTRODUCTION Sodium channel inhibitors have emerged as promising protective agents in various types of neuroinflammatory and neurodegenerative diseases. They have shown efficacy in diverse animal models including, but not limited to, experimental autoimmune encephalomyelitis (EAE; Lo et al ., 2003 ; Bechtold et al ., 2004 ; Bechtold et al ., 2005 ; Bechtold et al ., 2006 ; Morsali et al ., 2013 ) and experimental Parkinson’s disease ( Sadeghian et al ., 2016 ). Moreover, clinical trials suggest promise for treating multiple sclerosis ( Kapoor et al ., 2010 ; Gnanapavan et al ., 2013 ), optic neuritis ( Raftopoulos et al ., 2016 ) and Alzheimer’s disease ( Golmohammadi et al ., 2024 ). These studies have tested a range of drugs that have the common property of blocking voltage-gated sodium channels, including carbamazepine ( Al-Izki et al ., 2014 ), flecainide ( Bechtold et al ., 2004 ; Bechtold et al ., 2005 ; Morsali et al ., 2013 ), lamotrigine ( Bechtold et al ., 2006 ; Kapoor et al ., 2010 ; Gnanapavan et al ., 2013 ), oxcarbazepine ( Al-Izki et al ., 2014 ), phenytoin ( Lo et al ., 2003 ), riluzole ( Simard et al ., 2012 ; Wilson & Fehlings, 2014 ; Golmohammadi et al ., 2024 ) and safinamide ( Sadeghian et al ., 2016 ). Importantly, while it is accepted that all drugs have some off-target effects, the above compounds have the marked advantage of being safe for chronic administration in humans, with relatively benign side-effects. Individuals with Alzheimer’s disease have a higher incidence of epilepsy compared to their age-matched counterparts without the disease ( Bell et al ., 2011 ). As a result, various drugs have been tested on transgenic mouse models of Alzheimer’s disease in relation to seizure activity, with a range of effects ( Ziyatdinova et al ., 2011 ; Sanchez et al ., 2012 ; Verret et al ., 2012 ). On the other hand, it should be noted, in the case of treating epilepsy with anticonvulsants, there is little evidence that this prevents development of Alzheimer’s disease ( Carter et al ., 2007 ). However, this may be because epilepsy itself increases the risk of Alzheimer’s disease. Whether decreasing Na + channel activity would alter other aspects of the progression of the disease, in the absence of epilepsy, has not been tested. Amyloidβ, which is released in an activity-dependent manner at synapses, increases glutamate release probability ( Abramov et al ., 2009 ). This observation implies a feed forward loop that might lead to ever increasing levels of Amyloidβ ( Cirrito et al ., 2008 ; Abramov et al ., 2009 ). Therefore, disrupting this cycle may offer therapeutic advantages. Moreover, increased glutamate release has been described in a range of mouse models of Alzheimer’s disease, even before plaques become evident ( Busche et al ., 2012 ; Cummings et al ., 2015 ; Benitez et al ., 2021 ). Other evidence for hyperactivity has also been reported and this activity has been shown to be reversed by Na + channel inhibitors ( Ciccone et al ., 2019 ). Notably, a recent study in humans has associated such hyperactivity with the development of neurofibrillary tangles ( Giorgio et al ., 2024 ). However, the effects of modulating such activity on the development of pathology has not been investigated. We have therefore used two approaches to inhibit Na + channel activity through the chronic administration of either: 1. phenytoin, a long established anticonvulsant drug that blocks high-frequency action potentials that underlie the abnormal activity associated with seizures, while sparing normal brain activity ( Yaari et al ., 1986 ); or 2. GS967, a non-inactivating sodium channel blocker; that preferentially blocks the Na + channel late current rather than the peak current ( Anderson et al ., 2014 ). To investigate potential benefits of these Na + channel inhibitors, we have used two mouse models to examine effects on different disease pathologies. Firstly, to address the earliest stages of Alzheimer’s disease, we tested the effects of administration of Na + channel inhibitors on plaques in the APPKI mouse App NLGF/NLGF ( Saito et al ., 2014 ). We hypothesised that disrupting the feed forward loop of activity-dependent release of Amyloidβ might be beneficial. Secondly, as a proxy for the later clinical stages of tauopathies such as Alzheimer’s disease, we observed the development of tau tangles in TauD35 P301L mice ( Joel et al ., 2018 ), a model of frontotemporal dementia with parkinsonism (FTDP). We thus investigated whether interfering with the observed association of hyperactivity with Tau pathology ( Giorgio et al ., 2024 ) could alter the development of tangles. Neither of these mouse models has been reported to feature detectable epileptic episodes. Hence we are not investigating the role of epilepsy in Alzheimer’s disease but rather the role of hyperactivity and whether decreasing this activity could be a potential therapeutic strategy. Na + channel antagonists have also been reported to have potent effects in suppressing the pro-inflammatory activation of microglia within the brain ( Craner et al ., 2005 ; Sadeghian et al ., 2016 ), which is especially important given the growing evidence regarding microglial activation and proliferation in Alzheimer’s disease. In this context, we have also investigated whether the drugs influence the microglial proliferation that has previously shown to be in response to proximity to plaques and, to a lesser degree, tangles ( Matarin et al ., 2015 ; Chen et al ., 2020 ; Wood et al ., 2022 ). MATERIALS AND METHODS Animal models All mice were housed in groups of 2-5 animals in enriched environments, or occasionally single housed for a maximum of 24 hours at the Biological Services Unit of University College London. Access to food and water was ad libitum and mice were kept on a 12-hour light/dark cycle. All procedures were performed in accordance with the United Kingdom Animals (Scientific Procedures) Act 1986. APP knock in mice Male homozygous App NL-G-F/NL-G-F knock-in mice (NLGF) aged 3-3.5 months were used. These mice have a humanised Amyloidβ sequence within App and harbour Swedish (KM670/671NL), Beyreuther/Iberian (I716F) and Arctic (E694G) mutations ( Saito et al ., 2014 ). In the hippocampi of NLGF mice Amyloidβ plaques are first detectable at around 2 months ( Saito et al ., 2014 ). For further characterisation of these mice see ( Benitez et al ., 2021 ). TauP301L mice In a separate series of experiments to study the development of Tau pathology the mice used were transgenic for human Tau with a P301L mutation driven by the CaMKII promoter. This mutation causes frontotemporal dementia with parkinsonism linked to chromosome 17. These mice were developed by GlaxoSmithKline and it is now known that there are mice with two different transgene copy numbers ( Joel et al ., 2018 ). The line with high copy number and higher Tau levels were used for this study. Tau tangle-like pathology first appears at 8 months of age in these mice, and they reach severe neurodegeneration with a hunched, piloerect, and akinesic phenotype at about 17 months of age. According to Home Office requirements, mice were closely monitored and killed when the neurodegenerative phenotype became evident. The brain was immediately dissected out, and one hemisphere of the brain was drop fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) for 24 hours and then stored in 30% sucrose, 0.03% NaN 3 in PBS at 4°C. Chronic Administration of Drugs Two Na + channel inhibitors were investigated in this experiment: phenytoin and GS967. The drugs were administered orally through supplementation in chow. For investigation of early plaque development in the App NL-G-F/NL-G-F mice supplemented chow was available ad libitum from weaning at 3 weeks of age. For investigation of tau tangles in TauP301L mice supplemented chow was available ad libitum from 15 months of age. Age matched mice of both genotypes were administered the same chow, without drugs as controls. All other conditions remained the same. Drug doses used were 336 mg/kg of diet for phenytoin and 8 mg/kg of diet for GS967. Drug dosage was determined with reference to previous studies ( Craner et al ., 2005 ; Anderson et al ., 2014 ). Immunohistochemistry One brain hemisphere from each animal was drop fixed in 4% paraformaldehyde in PBS for 24 hours and then stored in 30% sucrose, 0.03% NaN 3 in PBS at 4°C. Hemispheres were cut to optimise sections transverse to the hippocampus and embedded in OCT compound (BDH, Poole, UK), frozen, and stored until use at -80°C. Frozen cryostat sections (15 µm) were mounted onto Superfrost Plus slides (VWR International, UK) and kept at -80°C until staining. Brain sections were labelled for MC1 using immunohistochemistry. The primary antibody and the corresponding secondary antibody are given in Table 1 . Slides were air dried overnight before any histology. Sections were rehydrated by washing in PBS buffer. Non-specific binding was blocked using 5% goat serum in 0.1 M PBS for at least 30 mins. Sections were incubated with primary antibody overnight at 4°C. Primary antibodies were detected using a secondary antibody fused to AlexaFluor488 or AlexaFluor594 at a 1:500 dilution or by diaminobenzidine staining using standard methods ( Table 1 ). Incubation of secondary antibodies was for two hours at room temperature. Three PBS washes were performed between each step. Sections were coverslipped with Vectashield (Vector Laboratories) containing DAPI. View this table: View inline View popup Download powerpoint Table 1 Details of antibodies used. Imaging Slides were imaged with an EVOS Auto FL Microscope (Life Technologies) using a x20 objective including the whole hippocampus and some surrounding cortex. Statistical analysis Quantitative data are presented as mean ± standard error of the mean (SEM) throughout. Sample sizes are referred to as number of animals for each experimental group. Outliers were classified as data more than two standard deviations away from the mean and were excluded from further analysis. Two-way analysis of variance (ANOVA) and unpaired t-tests were used to assess significance between groups. Tukey post-hoc tests were used throughout. Differences were considered statistically significant when p<0.05. All statistical tests and plots were performed using Prism v10 (Graphpad). RESULTS Effects of chronic treatment with Na + channel inhibitors on mice with plaques Na + channel inhibitors affect the early development of plaques in App NL-G-F/NL-G-F mice To assess the effects of inhibiting Na + channels on the early deposition of plaques, App NL-G-F/NL-G-F mice were fed either normal mouse chow or chow containing 340 mg/kg of diet phenytoin or 8 mg/kg of diet GS967 from weaning (from 3 weeks of age, before plaques are evident) until use in experiments at 3 – 3.5 months of age. The weights of 3 mice from each treatment group were measured regularly. Growth rates were not significantly different between groups. Weight gain over a 6-week period was: control diet, 10.2 ± 0.9 g; Phenytoin, 11.6 ± 1.2 g; GS967, 10.6 ± 0.9 g. Plaques were still fairly sparse at the time of the analysis. Although there was no significant main effect of treatment on plaque density (data not shown), there was a strong trend for treatment to affect median plaque area (one-way ANOVA, treatment p = 0.055 with a significant effect of phenytoin, p = 0.035; Fig. 1A-C ). The pooled distribution of plaque sizes was significantly affected by the chronic ingestion of phenytoin with the distribution being skewed towards a higher proportion of very small plaques ( Fig 1b ) compared to control mice, with control mice showing the largest plaques. In control mice, a small proportion of large plaques (180 – 1306 µm 2 ) were seen in 4 of the 5 control mice, whereas only 1 mouse in each of the treatment groups showed one or two plaques in this range (192 – 216 µm 2 ). (Control n = 5; treatments n = 4 animals). Download figure Open in new tab Figure 1 Treatment with phenytoin results in a higher proportion of small plaques and prevent the occurrence of the largest plaques. A. Mean area of individual plaques; B. Frequency distribution of plaque sizes; C. Percentage of hippocampus covered by plaque. Individual points represent individual mice; columns represent mean ± S.E.M. Asterisks represent posthoc analysis *p < 0.05, **p < 0.01 Effects of chronic treatment with Na + channel inhibitors on mice with neurofibrillary tangles Chronic treatment with Na + channel inhibitors prevented loss of brain weight but did not improve life span in TauP301L mice The cognitive deficits of Alzheimer’s disease only become apparent once neurofibrillary tangles begin to build up in the hippocampus ( Nelson et al ., 2012 ; Edwards, 2019 ). As treatment to prevent the progression of disease would be more likely to be applicable to these later stages of disease, once symptoms became apparent, we concentrated our study on the development of neurofibrillary tangles. TauP301L mice were fed GS967 or phenytoin or control diet from 15 months old until the neurodegenerative phenotype was observed, at which point animals were culled. At this age mouse growth has plateaued and there was no difference over a 6-week period in the weight of mice on different diets. The neurodegenerative phenotype was visually evident as hunched posture, piloerection and complete immobility. As a rough assessment of the degree of neurodegeneration the fixed brains of the mice were blotted dry and weighed before sectioning. Mice reached the neurodegenerative phenotype between 16.4 and 19.6 months. There was no significant difference between the treatment groups (age in months): controls, 18.21 ± 0.44, n = 7; GS967, 16.93 ± 0.27, n = 4; phenytoin, 17.93 ± 0.17, n = 3; Fig. 2A )). The hemisphere of the brain to be used for immunohistochemistry was weighed at the endpoint. On the control diet, TauP301L mice were found to have a significantly lower brain weight than WT mice but this decrease was prevented by both drugs ( Fig. 2B,C ). Download figure Open in new tab Figure 2 A. Treatment with Na + channel inhibitors did not significantly change the age of reaching the neurodegenerative phenotype. B TauP301L mice had significantly lower brain weights than WT mice but this difference was lost after treatment with either drug. C. Pooling the brain weights of mice treated with inhibitors shows no significant difference between brain weights of WT and TauP301L mice. Asterisks represent posthoc analysis ** p < 0.01 Chronic treatment with Na + channel inhibitors decreased tangle load in TauP301L mice To assess the effect of the two Na + channel inhibitors on the development of neurofibrillary tangles, sections were labelled with an MC1 antibody which labels paired helical filaments ( Jicha et al ., 1997 ). Positive labelling that clearly surrounded a DAPI nucleus was considered indicative of the presence of a neurofibrillary tangle. Tangles were manually counted per Area of Interest (AOI, 240 µm x 400 µm) in the cell body layer of each of the primary hippocampal regions (dentate gyrus, CA3 and CA1) with AOIs from 2 hippocampal sections per animal averaged to give n = 1. A trend was seen across all regions to show a decrease in MC1 positive cell bodies when the two drug treatments were analysed separately (2-way ANOVA main effect treatment, p = 0.07). Interestingly there was a significant difference between hippocampal areas, with the dentate gyrus showing significantly more tangles than the other regions (main effect of region, p = 0.02). As sample sizes for the treatment groups were small, the two treatment groups were pooled. Pooling the treatment groups revealed a significant decrease in the density of MC1 positive cell bodies (p < 0.02; Fig. 3 ). Download figure Open in new tab Figure 3 Na + channel inhibitors decrease the density of neurofibrillary tangles. A. Images of DAPI-stained (blue) and MC1 (green) positive neurofibrillary tangles in aged hTauP301L mice, fed with the treatment indicated. B,C. Counts of neurofibrillary tangles in AOIs (400µm x 240µm) in the cell body layer of different regions of the hippocampus. B. Effects of individual treatments do not reach statistical significance. C. Pooling the results from the two Na + channel inhibitors shows a significant decrease in tangle load. 2-way analysis of variance: main effects of region (p = .0004) and treatment (p = 0.02). Asterisks represent posthoc analysis * p < 0.05. Treatment with Na + channel inhibitors did not affect microgliosis in TauP301L mice Microglia density increased in TauP301L mice compared to WT mice but this difference was not affected by treatment with individual Na + channel inhibitors As microglia are clearly important in the progression of various forms of dementia we assessed the density of IBA1-positive microglia in WT versus TauP301L mice in the different layers of the CA1 region and in the dentate gyrus. In the TauP301L mice there is an increase in microglial number compared to WT in both CA1 region and in the dentate gyrus but no significant difference is seen with either drug treatment. Counts were made in different CA1 layers and in both CA1 and dentate gyrus with similar results in all regions ( Fig. 4 ). As the trend for dentate gyrus was in the same direction for these two related treatments, we again pooled the data to assess whether there was an overall effect of Na + channel inhibitors again revealing a significant effect of Na + channel inhibitors, (p = 0.03; Fig. 4D ). This suggests that the inhibition of Na + channels decreases the response of the microglia in the TauP301L mice bringing it almost back to WT levels which could have important effects on disease progression. Download figure Open in new tab Figure 4 Treatment with Na + channel inhibitors decreased microglial proliferation in the dentate gyrus of TauP301L mice A. Iba1 stained cells were counted in fixed tissue in different regions of the hippocampus. B-C. Results from CA1 and dentate regions respectively. D. Pooled data from the two treatment groups showed a significant effect of inhibiting Na + channels. 3 sections per mouse were analysed and the results averaged. Individual data points refer to means for individual animals. Asterisks represent posthoc analysis* p < 0.05, ** p < 0.01, **** p < 0.0001. Considering that the differences in both neurofibrillary tangle density and microglial density were in the same direction with the two treatments but showed considerable variation, we investigated whether the density of tau tangles correlated with the density of microglia in the same region. While a significant correlation was observed if all groups were pooled, the correlation was clearly driven by the treatment groups, with no correlation being observed in the control group alone ( Fig. 5 ). Not surprisingly such correlations were not observed in the CA1 region where changes in these variables were less consistent. Download figure Open in new tab Figure 5 In dentate gyrus, the density of neurofibrillary tangles correlated with the density of microglia. Pooling data from all groups resulted in a significant correlation (Pearson correlation 0.64; p < 0.02). Correlations did not reach significant in individual treatment groups (n = 3-4) but if Na + channel inhibitors were pooled, to compare equal sample sizes (n = 7) between pooled treatment and controls, a strong correlation was observed for pooled treatment groups (Pearson correlation r = 0.87; p = 0.01). The control group alone showed no significant correlation (Pearson correlation 0.25; p = 0.58). Control diet open black circles; GS967 filled blue circles; phenytoin filled yellow circles. Linear regression lines and 95% confidence intervals shown for control diet (black) and pooled treatments (green). DISCUSSION Modulating Na + currents with phenytoin or GS967 had subtle effects on both plaque deposition and the density of neurofibrillary tangles. This study investigated the initial deposition of plaques in APPKI mice ( App NLGF/NLGF ) on the basis that the release of Amyloidβ is activity-dependent ( Abramov et al ., 2009 ) and thus administration of inhibitors of Na + channels could influence the initial seeding of plaques. Small plaques are first detectable in the App NLGF/NLGF from 2 months of age and so have only been developing for a short period by the age tested (3.5 months). However, a surprising spread of plaque sizes was evident in the mice on control diet. This heavily skewed distribution was truncated in the mice treated with Na + channel inhibitors, suggesting that the ongoing growth of the plaque, after initial seeding, continues to be activity-dependent. Other parameters including the density and overall plaque coverage were not changed. However, it is important to note that plaque number and coverage at this age are relatively low and rapidly increasing which likely contributed to the wide variability of the measurement. In contrast to the amyloid mice the transgenic TauP301L mice were studied at the end stage of neurodegeneration. A cautionary note should be added as to the validity of the model. This, like all the previous tauopathy models, is an overexpression model of mutated Tau. We have published evidence that the overexpression itself may be an important factor in the build-up of Tau tangles and in the age of neurodegeneration in these models ( Joel et al ., 2018 ). The amount of Tau that can bind to the microtubules may be related to activity and so this could interact with these treatments. Furthermore, this is a model for frontotemporal dementia with parkinsonism linked to chromosome-17, rather than Alzheimer’s disease; however, the effects of tau tangles are most likely common to many related neurodegenerative diseases. There was a strong trend for a decrease in tangle load after treatment with phenytoin or GS967 and this reached significance when the treatment groups were pooled for analysis. Moreover, the decreased brain weight measured in the mice on control diet was prevented by the Na + channel inhibitors although this did not translate to an increase in healthy life span. Indeed, all groups of Tau mice displayed the neurodegenerative phenotype at the same mean age independent of treatment. This would suggest that the tangle load or neurodegeneration as measured by brain weight were not the only driving forces for the neurodegenerative phenotype. Alternatively, these putatively protective changes were not sufficient to impact the phenotype. One explanation for a decrease in neurofibrillary tangles in the treated mice could be that the dystrophic neurones containing hyperphosphorylated Tau were more efficiently removed by microglia under these conditions. However, this seems unlikely as, although there was a proliferation of microglia in the Tau mice compared to controls, the trend was for this proliferation to be decreased in treated mice. As loss-of-function mutations in some anti-inflammatory microglial genes, such as TREM2 , increase the risk of Alzheimer’s disease ( Guerreiro et al ., 2013 ; Jonsson et al ., 2013 ), it is likely that microglial activity slows the development of the disease at early stages, while at later stages they may cause increased neurodegeneration through release of proinflammatory cytokines. It is interesting to note that, when individual mice are compared, microglial density correlates strongly with neurofibrillary tangle load, but only in treated animals. The lack of correlation in the control group is consistent with previous observations in untreated mice that when mice with different tangle loads are compared, there is only a weak correlation with increased expression of microglial genes ( Matarin et al ., 2015 ). The strong correlation in the presence of Na + channel inhibitors may suggest a role of microglial Na + channels in this context. If microglial density were simply a response to tangle load then, although the tangle load might be influenced by decreased neuronal activity in treated mice, the correlation between tangle load and microglial density should not be changed by treatments. However, as the correlation is only seen in the treated mice, this suggests that a change in microglial activity may be influencing the tangle load. Indeed it has been reported that microglia express Nav1.6 Na + channels and that Na + channel inhibitors can reduce microglial activation ( Black et al ., 2009 ; Black & Waxman, 2012 ; Morsali et al ., 2013 ; Sadeghian et al ., 2016 ). This is a particularly interesting finding in the light of the likely protective effects of microglial activation around plaques in earlier stages of disease progression as evidenced by the increase in risk of developing Alzheimer’s disease when microglial response to plaques is defective such as in individuals with certain variants of the microglial TREM2 gene ( Guerreiro et al ., 2013 ; Jonsson et al ., 2013 ; Liu et al ., 2020 ). It is thus surprising that interfering with microglial function would in this case be protective, with this difference, presumably relating to age and possibly specifically in relation to neurofibrillary tangles. Further functional studies would be needed to confirm the role of microglial Na + channels in this context but it may confirm that treatments related to microglial activation could be valuable in various tauopathies. However, in Alzheimer’s disease this would relate specifically only to late stage disease with microglial activation having an important protective function in early disease ( Edwards, 2019 ). Footnotes Funding: Alzheimer’s Research UK Pilot grant to FAE, KJS and PW; UK Medical Research Council grant to KJS; ARUK funds the UCL Drug Discovery Institute; Multiple Sclerosis Society grant to KJS. REFERENCES ↵ Abramov , E. , Dolev , I. , Fogel , H. , Ciccotosto , G.D. , Ruff , E. & Slutsky , I. ( 2009 ) Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses . Nat Neurosci , 12 , 1567 – 1576 . 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