Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice
Open accessAbstract
Synapse or dendritic spine loss is the strongest correlate of cognitive decline in Alzheimer’s disease (AD), and neurofibrillary tangles, but not amyloid-β plaques, associate more closely with transition to mild cognitive impairment. Yet, how dendritic spine architecture is affected by hyperphosphorylated tau is still an ongoing question. To address this, we combined cell and biochemical analyses of the Tau P301S mouse line (PS19). Individual pyramidal neurons in the hippocampus and medial prefrontal cortex (mPFC) were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and 3D morphometry analysis. In the hippocampus, PS19 mice and non-transgenic (NTG) littermates displayed equivalent spine density at 6 and 9 months, but both genotypes exhibited age-related thin spine loss. PS19 mice exhibited significant increases in synaptic tau protein levels and mean dendritic spine head diameter with age. This suggests that CA1 pyramidal neurons in PS19 mice may undergo spine remodeling in response to tau accumulation and age. In the mPFC, spine density was similar among PS19 mice and NTG littermates at 6 and 9 months, but age-related reductions in synaptic tau levels were observed among PS19 mice. Collectively, these studies reveal brain region-specific changes in dendritic spine density and morphology in response to age and the presence of hyperphosphorylated tau in the PS19 mouse line.
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Written from the paper’s full text.
TL;DR
In PS19 tauopathy mice, hippocampal CA1 pyramidal neurons showed age-related thin spine loss but increased mean dendritic spine head diameter and synaptic total human tau from 6 to 9 months, whereas mPFC neurons showed no robust spine morphology changes despite decreased synaptic human tau with age. The authors conclude that hyperphosphorylated tau does not drive robust dendritic spine degeneration in PS19 mice and that remodeling responses are brain-region-specific.
Key findings
- In the hippocampus, PS19 and NTG littermates had equivalent spine density at 6 and 9 months, but both genotypes showed age-related reductions in spine density driven by decreased thin spine density; basal dendrites from 9-month animals had lower spine density due to reduced thin spines.
- PS19 mice exhibited increased mean dendritic spine head diameter with age in the hippocampus on apical dendrites, basal dendrites, and all dendrites collectively, with no differences in spine length.
- Hippocampal synaptosomes from PS19 mice showed a significant increase in total human tau from 6 to 9 months, while human tau phosphorylated at S199, T231, or S396 was similar at both ages; soluble whole homogenate and insoluble fractions also showed similar tau levels at 6 and 9 months.
- In the mPFC, spine density and morphology were similar between PS19 and NTG mice at 6 and 9 months, but PFC synaptosomes showed a significant reduction in total human tau with age, with no significant changes in tau phosphorylated at S199, T231, or S396.
Methods
- PS19 tauopathy mice and non-transgenic littermates were aged to 6 and 9 months; both male and female mice were used, and immunohistochemistry used NeuN and AT8 antibodies in hippocampus and prelimbic mPFC.
- Individual CA1 and mPFC layer 2/3 pyramidal neurons were targeted for iontophoretic microinjection of Lucifer yellow, followed by high-resolution confocal microscopy, deconvolution, and Neurolucida 360 three-dimensional morphometry; animals needed at least 100 μm of reconstructed dendrite for spine density/morphology analyses.
- Synaptosomal fractions were isolated from hippocampus and PFC, with ELISAs for total human tau and human tau phosphorylated at S199, T231, and S396, plus Western blotting for PSD95, synaptophysin, and GAPDH; statistics used two-way ANOVA with Tukey’s multiple comparisons, unpaired t-tests with Holm’s correction, and Welch’s t-test when variance was unequal.
Limitations
- Stated: confocal microscopy has lower resolution than super-resolution or electron microscopy, so spine identification, measurement, and classification may be inaccurate; it fails to resolve short-necked spines and is more likely to miss spines in the z-direction, and absolute spine head and neck diameter measurements may be less reliable at or below the resolution limit.
- Stated: not every neuron sampled from PS19 mice may express the P301S human tau transgene, although AT8 staining showed the majority of NeuN+ cells in CA1 and prefrontal cortex were positive; the authors also note they may have selected time points too late to capture changes in phosphorylated tau.
- Evident: the study is correlational and does not establish causality between synaptic tau levels and dendritic spine remodeling; although both sexes were used, no sex-specific analyses are reported.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
25 of 53 cited sources checked · 10 supported · 2 flagged · accuracy not yet measured
- Premisecitation
Mice expressing human wildtype tau or human tau with a P301L mutation have greater percentages of silent neurons, based on in vivo calcium imaging.
“Mice expressing human wildtype tau or human tau with a P301L mutation have greater percentages of silent neurons, based on in vivo calcium imaging (Busche et al., 2019).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Busche et al., 2019 source
- Findingown data
In PS19 mice, there were no robust differences in spine density when PS19 mice were compared to NTG littermates, despite reported behavioral and electrophysiological deficits at the ages assessed.
“Although behavioral and electrophysiological deficits have been reported in the PS19 line at the ages assessed in our study (Yoshiyama et al., 2007, Takeuchi et al., 2011, Briggs et al., 2017, Chalermpalanupap et al., 2018), we did not observe robust differences in spine density when PS19 mice were compared to NTG littermates.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Yoshiyama et al., 2007 source
- cites Takeuchi et al., 2011 source
The Results sections on open-field behavior and sensorimotor gating report behavioral differences and altered prepulse inhibition in young P301S tau mice; the Methods place the prepulse-inhibition test at 16 weeks. Our copy does not report electrophysiological deficits. The spine-density comparison is the citing authors’ own finding, not a finding attributed to Takeuchi et al. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites Briggs et al., 2017 source
The Results section reports behavioral differences between PS19 and nontransgenic mice, including locomotor hyperactivity and spatial learning and memory deficits; Materials and Methods identifies the PS19 mice as 8–9 months old (page numbers unavailable). The cited paper does not report electrophysiological deficits in PS19 mice. The spine-density finding is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Synaptophysin, a presynaptic marker, was used for synapse quantification in two of the past studies.
“Furthermore, synaptophysin, a presynaptic marker, was used for synapse quantification in two of the studies (Yoshiyama et al., 2007, Crescenzi et al., 2014), whereas our methods assess the postsynaptic dendritic spine.”
Quote in the paperSubstantial claim1 of 2 sources checked - Premisecitation
There are intrinsic differences in spine turnover between the hippocampus and cortical regions, with spines in the hippocampus exhibiting more rapid and frequent remodeling and turnover in comparison to cortical spines.
“There are intrinsic differences in spine turnover between the hippocampus and cortical regions, with spines in the hippocampus exhibiting more rapid and frequent remodeling and turnover in comparison to cortical spines (Grutzendler et al., 2002, Trachtenberg et al., 2002, Holtmaat et al., 2005, Pfeiffer et al., 2018).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Grutzendler et al., 2002 source
- cites Trachtenberg et al., 2002 source
- cites Holtmaat et al., 2005 source
The spine-plasticity passages (section labeled Introduction; page unavailable) compare turnover in two cortical regions, S1 and visual cortex. Our copy does not compare hippocampal with cortical spine turnover or establish that hippocampal spines remodel more rapidly and frequently; searches for those comparisons found no such passage. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Premisereasoning
Past studies that reported synapse loss in PS19 mice relied on immunohistochemical staining of synaptic markers, which does not yield image resolution comparable to the methods employed here.
“However, these studies relied on immunohistochemical staining of synaptic markers, which does not yield image resolution that is comparable to the methods employed here.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Yoshiyama et al., 2007 source
- cites Crescenzi et al., 2014 source
The Methods (§2.4) describe immunohistochemical staining for synaptophysin, a synaptic marker, and the Results (§3.3) report lower synapse density in the CA3 of PS19 mice. The paper does not compare the resolution of those staining images with the citing study’s methods; its Discussion compares GluCEST resolution with conventional ¹H MRS instead. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Dejanovic et al., 2018 source
- Premisecitation
Synapse or dendritic spine loss correlates more strongly with cognitive impairment than amyloid-β plaques or neurofibrillary tangles in Alzheimer's disease.
“Synapse or dendritic spine loss correlates more strongly with cognitive impairment than Aβ plaques or NFTs in AD (DeKosky and Scheff, 1990, Terry et al., 1991, Boros et al., 2017, Chen et al., 2018).”
Quote in the paperSubstantial claim1 of 3 sources checked - Premisecitation
Recent positron emission tomography imaging of tau indicates a stronger correlation of tau changes with cognitive impairment and transition to mild cognitive impairment.
“Older studies of 11C-Pittsburgh compound B imaging suggested that only 13% of cognitively normal individuals that are positive for Aβ will transition to mild cognitive impairment (MCI) or AD (Rowe et al., 2013), whereas recent positron emission tomography (PET) imaging of tau indicates a stronger correlation of tau changes with cognitive impairment and transition to MCI (Hanseeuw et al., 2019).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hanseeuw et al., 2019 source
- Interpretationcitation
Our findings in the hippocampus support in vitro studies showing that hyperphosphorylated tau does not induce spine loss in primary hippocampal neuron cultures or organotypic slices.
“Our findings in the hippocampus support in vitro studies showing that hyperphosphorylated tau does not induce spine loss in primary hippocampal neuron cultures or organotypic slices (Shahani et al., 2006, Hoover et al., 2010, Miller et al., 2014).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites Shahani et al., 2006 source
- cites Hoover et al., 2010 source
- cites Miller et al., 2014 source
The Results section reports that Aβ-treated primary hippocampal neurons showed tau mislocalization without a significant change in spine density over one to three days. This supports the culture finding, but the paper does not establish that hyperphosphorylated tau itself cannot induce spine loss, and it does not report that finding in organotypic slices. The Discussion notes that longer Aβ exposure may produce permanent spine loss; page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Soluble tau, rather than NFTs, is the pathologic tau species.
“Given the evidence that soluble tau, rather than NFTs, is the pathologic tau species (Santacruz et al., 2005, Yoshiyama et al., 2007, Kopeikina et al., 2012, Lasagna-Reeves et al., 2012, Polydoro et al., 2014, Ghag et al., 2018)”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Santacruz et al., 2005 source
- cites Yoshiyama et al., 2007 source
- cites Kopeikina et al., 2012 source
The Conclusions and Future directions section favors soluble tau as more toxic to neuronal and synaptic function. But it also says there is evidence that fibrillar tau contributes to dysfunction and that a toxic role for NFTs is not excluded. The claim overstates the paper's position by treating soluble tau as the pathologic species rather than NFTs. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Tau, including phosphorylated tau, is present in presynaptic and postsynaptic compartments in the PS19 mouse model.
“Tau, including phosphorylated tau, is present in presynaptic and postsynaptic compartments in the PS19 mouse model (Yoshiyama et al., 2007, Dejanovic et al., 2018, McInnes et al., 2018).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Yoshiyama et al., 2007 source
- cites Dejanovic et al., 2018 source
- cites McInnes et al., 2018 source
In “Syngr3 Mediates Presynaptic Dysfunction in Hippocampal Neurons from a Tauopathy Mouse Model” (page unavailable), the paper reports that Tau P301S localizes to presynaptic terminals in PS19 hippocampal neurons. The Introduction discusses postsynaptic Tau generally, and the reported enrichment of phosphorylated Tau concerns Alzheimer’s patient brain, not PS19 mice. Our copy therefore does not establish postsynaptic or phosphorylated Tau localization in PS19 mice. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Findingown data
In PS19 mice, there were no robust effects of the P301S tau transgene on dendritic spine density or morphology on layer 2/3 mPFC pyramidal neurons at 6 or 9 months compared to NTG littermates.
“Overall, we did not observe any robust effects of the P301S tau transgene on dendritic spine density or morphology on layer 2/3 mPFC pyramidal neurons at 6 or 9 months in comparison to NTG littermates.”
Quote in the paperSubstantial claim - Findingown data
In the PFC of PS19 mice, levels of human tau phosphorylated at S199, T231, or S396 in soluble and insoluble fractions were similar at 6 and 9 months.
“PS19 mice displayed similar levels of total human soluble and insoluble tau, as well as human tau phosphorylated at S199, T231, or S396 at 6 and 9 months in the PFC (Fig. 9, E-L).”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Rests on an assumption: The methods used can detect total human tau and tau phosphorylated at S199, T231, and S396 with sufficient sensitivity to reveal differences if present.
- Findingown data
In the hippocampus of PS19 mice, synaptic tau protein levels increased with age.
“PS19 mice exhibited significant increases in synaptic tau protein levels and mean dendritic spine head diameter with age.”
Quote in the paperSubstantial claim - Findingown data
In hippocampal synaptosomes from PS19 mice, levels of human tau phosphorylated at S199, T231, or S396 were similar at 6 and 9 months.
“However, levels of human tau phosphorylated at S199, T231, or S396 in synaptosomes were similar at 6 and 9 months (Fig. 6, B-D).”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Rests on an assumption: The methods used can detect total human tau and tau phosphorylated at S199, T231, and S396 with sufficient sensitivity to reveal differences if present.
- Findingown data
NTG littermates showed little to no AT8 staining in the hippocampus at 6 and 9 months.
“NTG littermates showed little to no AT8 staining in the hippocampus at 6 and 9 months (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
Both NTG and PS19 mice exhibited a noticeable decline in NeuN+ cells in the prefrontal cortex at 9 months compared to 6 months.
“Additionally, both NTG and PS19 mice exhibited a noticeable decline in NeuN+ cells in the prefrontal cortex at 9 months compared to 6 months (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
In PS19 mice at 6 and 9 months, the vast majority of NeuN+ neurons in CA1 of the hippocampus and layers 2/3 of the prelimbic prefrontal cortex displayed robust hyperphosphorylated AT8+ tau (Ser202/Thr205).
“The vast majority of NeuN+ neurons displayed robust hyperphosphorylated AT8+ tau (Ser202/Thr205) in CA1 of the hippocampus and layers 2/3 of the prelimbic prefrontal cortex in PS19 mice at 6 and 9 months (Figs. 1 and 2).”
Quote in the paperSubstantial claim - Findingown data
In the medial prefrontal cortex of PS19 mice, age-related reductions in synaptic tau levels were observed.
“In the mPFC, spine density was similar among PS19 mice and NTG littermates at 6 and 9 months, but age-related reductions in synaptic tau levels were observed among PS19 mice.”
Quote in the paperSubstantial claim - Findingown data
In PFC synaptosomes from PS19 mice, no significant differences in levels of human tau phosphorylated at S199, T231, or S396 were detected between 6 and 9 months.
“No significant differences in levels of human tau phosphorylated at S199, T231, or S396 were detected (Fig. 9, B-D).”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Rests on an assumption: The methods used can detect total human tau and tau phosphorylated at S199, T231, and S396 with sufficient sensitivity to reveal differences if present.
- Findingown data
In PFC synaptosomes from PS19 mice, total human tau levels significantly decreased with age from 6 to 9 months.
“We observed a significant reduction of total human tau levels in PFC synaptosomes with age (Fig. 9A).”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Findingown data
In PS19 mice, levels of total human tau in soluble whole homogenate and insoluble fractions from the hippocampus were similar at 6 and 9 months.
“Levels of total human tau in the soluble whole homogenate and the insoluble fraction, as well as human tau phosphorylated at S199, T231, and S396, were similar at 6 and 9 months in PS19 mice (Fig. 6, E-L).”
Quote in the paperNot a substantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Findingown data
In PS19 mice, tau accumulation in hippocampal synaptic compartments from 6 to 9 months corresponds with an increase in mean dendritic spine head diameter among CA1 pyramidal neurons.
“Collectively, we found that tau accumulates in synaptic compartments in the hippocampus from 6 to 9 months, and this corresponds with an increase in mean dendritic spine head diameter among CA1 pyramidal neurons.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Findingown data
In hippocampal synaptosomes from PS19 mice, total human tau levels significantly increased from 6 to 9 months.
“We observed a significant increase in total human tau levels in hippocampal synaptosomes from 6 to 9 months (Fig. 6A).”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Findingown data
PS19 mice exhibited an increase in dendritic spine head diameter with age on apical dendrites, basal dendrites, and all dendrites collectively.
“However, PS19 mice exhibited an increase in dendritic spine head diameter with age on apical dendrites, basal dendrites, and all dendrites collectively (Fig. 4, J-L).”
- Also stated in: § Abstract · plain
“PS19 mice exhibited significant increases in synaptic tau protein levels and mean dendritic spine head diameter with age.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
In the PFC of PS19 mice, levels of total human soluble and insoluble tau were similar at 6 and 9 months.
“PS19 mice displayed similar levels of total human soluble and insoluble tau, as well as human tau phosphorylated at S199, T231, or S396 at 6 and 9 months in the PFC (Fig. 9, E-L).”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Findingown data
In the mPFC, densities of thin, stubby, and mushroom spines were similar between NTG and PS19 mice at 6 and 9 months of age.
“Additionally, the densities of thin, stubby, and mushroom spines were similar between NTG and PS19 mice at 6 and 9 months of age (Fig. 8B).”
Quote in the paperNot a substantial claim - Findingown data
In the mPFC, densities of thin, stubby, and mushroom spines on basal dendrites were similar between NTG and PS19 mice.
“The densities of thin, stubby, and mushroom spines on basal dendrites were similar between groups (Fig. 8F).”
Quote in the paperNot a substantial claim - Findingown data
In the medial prefrontal cortex, spine density was similar among PS19 mice and NTG littermates at 6 and 9 months.
“In the mPFC, spine density was similar among PS19 mice and NTG littermates at 6 and 9 months, but age-related reductions in synaptic tau levels were observed among PS19 mice.”
Quote in the paperSubstantial claim - Findingown data
The present study revealed that accumulation of hyperphosphorylated human tau in synaptosomes corresponded with an increase in mean dendritic spine head diameter with age in the hippocampus of PS19 mice.
“The present study revealed that accumulation of hyperphosphorylated human tau in synaptosomes corresponded with an increase in mean dendritic spine head diameter with age in the hippocampus of PS19 mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Findingown data
In PS19 mice, tau accumulates in synaptic compartments in the hippocampus from 6 to 9 months.
“Collectively, we found that tau accumulates in synaptic compartments in the hippocampus from 6 to 9 months, and this corresponds with an increase in mean dendritic spine head diameter among CA1 pyramidal neurons.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Findingown data
Immunohistochemistry on PS19 mice at 6 and 9 months of age demonstrated that the majority of NeuN+ cells in CA1 and the prefrontal cortex are overwhelmingly positive for AT8 staining.
“Our immunohistochemistry on PS19 mice at 6 and 9 months of age demonstrated that the majority of NeuN+ cells in CA1 and the prefrontal cortex are overwhelmingly positive for AT8 staining (Figs. 1 and 2).”
Quote in the paperSubstantial claim - Findingown data
On basal dendrites in the mPFC, spine length was similar between NTG and PS19 mice.
“On basal dendrites, spine length was similar between groups (Fig. 8I).”
Quote in the paperNot a substantial claim - Findingown data
There were no measurable differences in levels of tau phosphorylated at S199, T231, or S396 in synaptosomes or insoluble fractions from PS19 mice at 6 months and 9 months of age by the methods employed herein.
“There were no measurable differences in levels of tau phosphorylated at S199, T231, or S396 in synaptosomes or insoluble fractions from PS19 mice at 6 months and 9 months of age by the methods employed herein.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Rests on an assumption: The methods used can detect total human tau and tau phosphorylated at S199, T231, and S396 with sufficient sensitivity to reveal differences if present.
- Findingown data
In PS19 mice, levels of human tau phosphorylated at S199, T231, and S396 in soluble whole homogenate and insoluble fractions from the hippocampus were similar at 6 and 9 months.
“Levels of total human tau in the soluble whole homogenate and the insoluble fraction, as well as human tau phosphorylated at S199, T231, and S396, were similar at 6 and 9 months in PS19 mice (Fig. 6, E-L).”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Rests on an assumption: The methods used can detect total human tau and tau phosphorylated at S199, T231, and S396 with sufficient sensitivity to reveal differences if present.
- Findingown data
AT8+ neurons in the prefrontal cortex were observed in 9-month-old NTG littermates.
“However, AT8+ neurons in the prefrontal cortex were observed from 9 month old NTG littermates, suggesting that an increase in phosphorylation of endogenous tau occurs with age in the prefrontal cortex, but not CA1 (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
In the mPFC, spine length was similar between NTG and PS19 mice at 6 and 9 months of age.
“Spine length was similar between NTG and PS19 mice at 6 and 9 months of age (Fig. 8G).”
Quote in the paperSubstantial claim - Interpretationown data
Our data suggest these architectural changes could be driven by tau-related disease processes.
“and our data suggest these architectural changes could be driven by tau-related disease processes.”
Quote in the paperSubstantial claim - Study design and conductown data
Synaptosome fractions isolated from the hippocampus of PS19 mice were enriched for both presynaptic and postsynaptic proteins.
“The synaptosome fractions are enriched for both presynaptic and postsynaptic proteins.”
Quote in the paperSubstantial claim - Study design and conductcitation
Based on comparisons with serial section transmission electron microscopy studies, the protocol used here results in accurate measurements of dendritic spine length, volume, and density.
“Based on comparisons with serial section transmission electron microcopy studies, the protocol used here results in accurate measurements of dendritic spine length, volume, and density (Dumitriu et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dumitriu et al., 2011
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
These differing observations may represent brain region-specific differences in response to tau accumulation.
“These differing observations may represent brain region-specific differences in response to tau accumulation.”
Quote in the paperSubstantial claim - Study design and conductnone given
The combination of confocal laser scanning microscopy and deconvolution employed in this study improves the resolution of confocal z-stacks.
“However, the combination of confocal laser scanning microscopy and deconvolution employed in this study improves the resolution of confocal z-stacks.”
Quote in the paperSubstantial claim - Interpretationown data
CA1 pyramidal neurons in PS19 mice may undergo spine remodeling in response to tau accumulation and age.
“This suggests that CA1 pyramidal neurons in PS19 mice may undergo spine remodeling in response to tau accumulation and age.”
Quote in the paperSubstantial claim - Study design and conductreasoning
Absolute measurement of spine head diameter and neck diameter may be less reliable, especially if the true size of these structures lies at or below the resolution limit.
“Absolute measurement of spine head diameter and neck diameter may be less reliable, especially if the true size of these structures lies at or below the resolution limit.”
Quote in the paperNot a substantial claim - Interpretationreasoning
In PS19 mice, a reduction of total human tau levels in PFC synaptosomes does not correlate with changes in dendritic spine density or morphology among layer 2/3 pyramidal neurons in the mPFC.
“Together, these results suggest that a reduction of total human tau levels in synaptosomes does not correlate with changes in dendritic spine density or morphology among layer 2/3 pyramidal neurons in the mPFC of PS19 mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
- Study design and conductreasoning
Confocal microscopy can yield inaccuracies with respect to spine identification, measurement, and classification.
“Therefore, confocal microscopy can yield inaccuracies with respect to spine identification, measurement, and classification.”
Quote in the paperNot a substantial claim - Interpretationown data
Changes in dendritic spine density and morphology in response to age and hyperphosphorylated tau in the PS19 mouse line are brain region-specific.
“Collectively, these studies reveal brain region-specific changes in dendritic spine density and morphology in response to age and the presence of hyperphosphorylated tau in the PS19 mouse line.”
Quote in the paperSubstantial claim - Premisecitation
The PS19 mouse line overexpresses 1N4R human tau with the frontotemporal dementia-associated P301S mutation under the control of the mouse prion protein promoter.
“The PS19 mouse line overexpresses 1N4R human tau with the frontotemporal dementia-associated P301S mutation under the control of the mouse prion protein promoter (Yoshiyama et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yoshiyama et al., 2007 source
- Study design and conductown data
Based on very low levels of GAPDH, the synaptosome fractions likely contained only minor amounts of proteins from other cellular compartments.
“Based on the very low levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) present, it is likely that the synaptosome fractions contained only minor amounts of proteins from other cellular compartments (Fig. 5, A-B).”
Quote in the paperSubstantial claim - Premisecitation
NFT-like inclusions are already present in PS19 mice at 6 months.
“and the fact that NFT-like inclusions are already present in PS19 mice at 6 months (Yoshiyama et al., 2007)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yoshiyama et al., 2007 source
- Interpretationown data
There may be brain region-specific differences in dendritic spine remodeling in response to hyperphosphorylated tau.
“Our findings suggest that hyperphosphorylated tau does not drive robust dendritic spine degeneration in PS19 mice, and that there may be brain region-specific differences in dendritic spine remodeling in response to hyperphosphorylated tau.”
Quote in the paperSubstantial claim - Interpretationreasoning
We may have selected time points at which it is too late to capture these changes.
“we may have selected time points at which it is too late to capture these changes.”
Quote in the paperSubstantial claim - Interpretationown data
Our findings suggest that hyperphosphorylated tau does not drive robust dendritic spine degeneration in PS19 mice.
“Our findings suggest that hyperphosphorylated tau does not drive robust dendritic spine degeneration in PS19 mice, and that there may be brain region-specific differences in dendritic spine remodeling in response to hyperphosphorylated tau.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 19
- May combine two claims. 28
Classified as probably not a substantial claim. May combine two claims.
PremisecitationDendritic spine density in the dorsolateral prefrontal cortex is inversely correlated with Braak stage in Alzheimer's disease, suggesting that tau pathology may be associated with spine loss.
“Notably, dendritic spine density in the dorsolateral prefrontal cortex is inversely correlated with Braak stage in AD, suggesting that tau pathology may be associated with spine loss (Boros et al., 2017, Boros et al., 2019).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites Boros et al., 2017 source
The Results report an inverse correlation between dorsolateral prefrontal cortex spine density and Braak stage across all cases, but explicitly state that there was no such correlation among AD cases. The Discussion reiterates that distinction. Thus, the paper does not support the claim that the inverse correlation was found in AD cases. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites Boros et al., 2019 source
The Results section, “Alzheimer’s disease pathology correlates with changes in spine density and morphology,” explicitly reports no correlation between overall DLPFC spine density and Braak stage in the cognitively normal cohort. It does report reduced density of the stubby-spine subtype with higher Braak stage, but that does not establish the claimed correlation for overall spine density or for patients with AD. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIn Alzheimer's disease, tau becomes hyperphosphorylated and mislocalizes to somatodendritic compartments.
“Under normal conditions, tau is primarily localized to axons and promotes formation and stabilization of microtubules; however, in AD, tau becomes hyperphosphorylated and mislocalizes to somatodendritic compartments (Avila et al., 2004, Ittner et al., 2010, Zempel et al., 2010).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Avila et al., 2004 source
The section “Tau phosphorylation and development” states that tau can become hyperphosphorylated in Alzheimer’s disease. The section “Cellular and subcellular localization of tau protein” places phosphorylated tau in somatodendritic compartments in developing neurons, but does not establish that tau mislocalizes there in Alzheimer’s disease. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Ittner et al., 2010 source
- cites Zempel et al., 2010 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn AD cases, dendritic and synaptic structural remodeling could represent compensatory plasticity responses during the transition from no cognitive impairment to MCI.
“Notably, in AD cases, dendritic and synaptic structural remodeling could represent compensatory plasticity responses during the transition from no cognitive impairment to MCI (Boros et al., 2017, Boros et al., 2019), and our data suggest these architectural changes could be driven by tau-related disease processes.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Boros et al., 2017 source
The Discussion says the observed spine changes could reflect synaptic structural changes during a transition from preclinical to symptomatic AD, which supports the proposed compensatory-plasticity interpretation. But the study compared cognitively normal people with AD pathology against people with AD dementia; it did not examine a transition specifically to MCI. The Discussion mentions MCI only as a possible outcome in an imaging study. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites Boros et al., 2019 source
The Discussion section on genetic and pathologic aspects of AD proposes that dendritic spine remodeling may help maintain cognitive function in cognitively normal people with AD pathology, and relates these mechanisms to a possible transition from preclinical to symptomatic AD. The Methods section states that all sampled cases were cognitively normal at death; the paper does not specifically establish remodeling during a transition to MCI. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationNon-super-resolution light microscopy-based methods fail to resolve short-necked spines and are more likely to fail to detect spines in the z-direction.
“Non-super-resolution light microscopy-based methods fail to resolve short-necked spines and are more likely to fail to detect spines in the z-direction (Pfeiffer et al., 2018; Tønnesen et al., 2014).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Pfeiffer et al., 2018 source
- cites Tønnesen et al., 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationCultured hippocampal neurons expressing P301L tau had deficits in synaptic transmission due to loss of surface AMPA receptors, but no gross reductions in spine density.
“Hoover et al. (2010) revealed that cultured hippocampal neurons expressing P301L tau had deficits in synaptic transmission due to loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but no gross reductions in spine density.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Hoover et al., 2010 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSpine morphology is highly dynamic and inextricably linked to synaptic activity and strength.
“Spine morphology is highly dynamic and inextricably linked to synaptic activity and strength (Yuste and Bonhoeffer, 2001, Matsuzaki et al., 2004, Hayashi and Majewska, 2005, Bertling et al., 2016, Bertling and Hotulainen, 2017, Efimova et al., 2017, Pfeiffer et al., 2018).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Yuste and Bonhoeffer, 2001 source
- cites Matsuzaki et al., 2004 source
- cites Hayashi and Majewska, 2005 source
The sections on rapid structural plasticity and functional significance describe continual changes in spine morphology, activity-dependent changes in geometry, and a positive correlation between spine expansion and enhanced synaptic transmission. But the paper also says direct evidence connecting structural and functional plasticity is limited and that whether structural plasticity is necessary for functional plasticity remains an open question. “Inextricably linked” overstates that evidence. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationUnder normal conditions, tau is primarily localized to axons and promotes formation and stabilization of microtubules.
“Under normal conditions, tau is primarily localized to axons and promotes formation and stabilization of microtubules; however, in AD, tau becomes hyperphosphorylated and mislocalizes to somatodendritic compartments (Avila et al., 2004, Ittner et al., 2010, Zempel et al., 2010).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Avila et al., 2004 source
- cites Ittner et al., 2010 source
- cites Zempel et al., 2010 source
The Figure 3 caption (Discussion; page unavailable) says tau is predominantly axonal in control neurons. The Discussion links tau’s detachment from microtubules to their destabilization, supporting a stabilizing role, but our copy does not establish the claim that tau promotes microtubule formation. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationThe increase in GluR2 AMPA receptor subunits would be expected to result in increased spine head diameter, which could explain observations in PS19 hippocampal spines.
“The increase in GluR2 AMPA receptor subunits would be expected to result in increased spine head diameter, which could explain our observations in PS19 hippocampal spines.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Williams et al., 2009 source
The Results section (“Expression of GluR2 mRNA and corresponding protein”; page unavailable) reports increased GluR2 receptor subunits in synaptoneurosomes from patients with incipient Alzheimer’s disease. The Discussion section (“GluR2 subunit regulation, oAβ and neuroplasticity”; page unavailable) does not say that increased GluR2 would enlarge spine heads. The PS19 observations are the citing authors’ own, but the proposed explanation for them is not established by this source. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataOverall, there was no effect of P301S tau genotype on spine density, length, or head diameter in CA1 of the hippocampus at 6 months or 9 months of age.
“Overall, there was no effect of P301S tau genotype on spine density, length, or head diameter in CA1 of the hippocampus at 6 months or 9 months of age.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the mPFC of PS19 and NTG mice, there was a significant main effect of age on dendritic spine density, but this effect did not result from specific differences between groups.
“We observed a significant main effect of age on dendritic spine density in the mPFC, although this effect did not result from any specific differences between groups (Fig. 8A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the mPFC, there was a significant main effect of genotype on basal spine density, but none of the groups differed significantly from each other.
“There was a significant main effect of genotype on basal spine density; however, none of the groups differed significantly from each other (Fig. 8E).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOn apical dendrites in the mPFC, there was a significant main effect of genotype on spine length, but none of the groups differed significantly from each other.
“On apical dendrites, there was a significant main effect of genotype on spine length, although none of the groups differed significantly from each other (Fig. 8H).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the mPFC, overall spine density on apical dendrites, as well as the density of individual spine types, was similar between NTG and PS19 mice.
“The overall spine density on apical dendrites, as well as the density of individual spine types, was similar between groups (Fig. 8, C-D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataBasal dendrites from 9-month-old animals had lower dendritic spine densities, due to a reduction in thin spine density.
“However, basal dendrites from 9 month old animals had lower dendritic spine densities, due to a reduction in thin spine density (Fig. 4, E-F).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThere were no differences in dendritic spine length between NTG and PS19 mice at either 6 or 9 months, and no age-dependent effects on spine length.
“We observed no differences in dendritic spine length between NTG and PS19 mice at either age, and observed no age-dependent effects (Fig. 4, G-I).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the mPFC, mean dendritic spine head diameter was similar between NTG and PS19 mice for all dendrites combined, as well as for apical and basal dendrites separately.
“In the mPFC, mean dendritic spine head diameter was similar between groups for all dendrites combined, as well as for apical and basal dendrites separately (Fig. 8, J-L).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth NTG and PS19 mice exhibited reductions in dendritic spine density with age, driven by decreased thin spine density.
“Both NTG and PS19 mice exhibited reductions in dendritic spine density with age, driven by decreased thin spine density (Fig. 4, A-B).”
- Also stated in: § Abstract · plain
“In the hippocampus, PS19 mice and non-transgenic (NTG) littermates displayed equivalent spine density at 6 and 9 months, but both genotypes exhibited age-related thin spine loss.”
Quote in the paperSubstantial claim- Also stated in: § Abstract · plain
May combine two claims.
Findingown dataIn PS19 mice, there was a lack of spine phenotypes in the mPFC despite a decrease in synaptic human tau levels with age in the prefrontal cortex.
“This contrasted with the lack of spine phenotypes in the mPFC, despite a decrease in synaptic human tau levels with age in the prefrontal cortex.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
May combine two claims.
Findingown dataThere was no difference in overall spine density or the densities of each spine type on apical dendrites of hippocampal CA1 pyramidal neurons.
“There was no difference in overall spine density or the densities of each spine type on apical dendrites (Fig. 4, C-D).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataWe observed tau in synaptosome fractions.
“As expected, we observed tau in synaptosome fractions.”
Quote in the paperNot a substantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
May combine two claims.
Findingown dataIn PS19 mice, synaptic tau levels declined with age in the PFC, with no notable alterations in dendritic spine density or morphology.
“In contrast to increased synaptic tau and enlargement of dendritic structures in the hippocampus, synaptic tau levels declined with age in the PFC of PS19 mice, with no notable alterations in dendritic spine density or morphology.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
May combine two claims.
Findingown dataIn this study, we observed an increase in mean dendritic spine head diameter and synaptic tau protein levels with age in the hippocampus of PS19 mice.
“In this study, we observed an increase in mean dendritic spine head diameter and synaptic tau protein levels with age in the hippocampus of PS19 mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
May combine two claims.
Findingown dataIn the PFC, there were no changes in spine density or morphology, despite a reduction in synaptic tau.
“In the PFC, there were no changes in spine density or morphology, despite a reduction in synaptic tau.”
Quote in the paperSubstantial claim- Rests on an assumption: Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
May combine two claims.
InterpretationreasoningPFC neurons in PS19 mice may lack the necessary machinery to structurally remodel dendritic spines in response to tau accumulation, possibly due to cell type-specific differences in gene expression.
“Therefore, PFC neurons in PS19 mice may lack the necessary machinery to structurally remodel dendritic spines in response to tau accumulation, possibly due to cell type-specific differences in gene expression.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEvery neuron sampled from PS19 mice may not express the P301S human tau transgene.
“Another limitation of this approach is that every neuron sampled from PS19 mice may not express the P301S human tau transgene.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationPS19 mice exhibit deficits in synaptic function, including impaired long-term potentiation in CA1 of the hippocampus.
“Moreover, despite the lack of robust spine loss observed in this study, PS19 mice exhibit deficits in synaptic function, including impaired long-term potentiation in CA1 of the hippocampus (Yoshiyama et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yoshiyama et al., 2007 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNeuron impalement within the medial prefrontal cortex and CA1 occurred randomly in a blind manner.
“Neuron impalement within the mPFC and CA1 occurred randomly in a blind manner.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataPS19 mice were compared with age- and sex-matched NTG littermate controls.
“We examined whether spine density and morphology in the hippocampus of 6 and 9 month old PS19 mice differed from age- and sex-matched NTG littermate controls.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMost excitatory synapses occur on dendritic spines, which are actin-rich protrusions on dendrites.
“Most excitatory synapses occur on dendritic spines, which are actin-rich protrusions on dendrites (Bertling and Hotulainen, 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bertling and Hotulainen, 2017 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationS199 and T231 are two of the earliest phosphorylated sites on tau in Alzheimer's disease.
“S199 and T231 are two of the earliest phosphorylated sites on tau in AD (Maurage et al., 2003, Luna-Munoz et al., 2007), and tau phosphorylated at S396 is found in paired helical filaments (Bramblett et al., 1993).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenELISA chromogen incubation times were modified to avoid saturation.
“Assays were conducted based on the protocol provided with each kit, with the exception of the chromogen incubation times, which were modified to avoid saturation: total tau (1 min 45 sec), pS199 tau (18 min), pT231 (30 min, as recommended), and pS396 tau (26 min).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAn increase in phosphorylation of endogenous tau occurs with age in the prefrontal cortex, but not CA1, of NTG mice.
“However, AT8+ neurons in the prefrontal cortex were observed from 9 month old NTG littermates, suggesting that an increase in phosphorylation of endogenous tau occurs with age in the prefrontal cortex, but not CA1 (Fig. 2).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationNFT-like tau inclusions have been reported in 6-month-old PS19 mice in both the hippocampus and prelimbic prefrontal cortex, with neuronal loss becoming evident at 9 months of age.
“NFT-like tau inclusions have been reported in 6 month old PS19 mice, in both the hippocampus and prelimbic prefrontal cortex, with neuronal loss becoming evident at 9 months of age (Yoshiyama et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yoshiyama et al., 2007 source
Classified as probably not a substantial claim.
PremisecitationOlder 11C-Pittsburgh compound B imaging studies suggested that only 13% of cognitively normal individuals positive for amyloid-β will transition to mild cognitive impairment or Alzheimer's disease.
“Older studies of 11C-Pittsburgh compound B imaging suggested that only 13% of cognitively normal individuals that are positive for Aβ will transition to mild cognitive impairment (MCI) or AD (Rowe et al., 2013), whereas recent positron emission tomography (PET) imaging of tau indicates a stronger correlation of tau changes with cognitive impairment and transition to MCI (Hanseeuw et al., 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rowe et al., 2013 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTau phosphorylated at S396 is found in paired helical filaments.
“S199 and T231 are two of the earliest phosphorylated sites on tau in AD (Maurage et al., 2003, Luna-Munoz et al., 2007), and tau phosphorylated at S396 is found in paired helical filaments (Bramblett et al., 1993).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bramblett et al., 1993 source
May combine two claims.
Interpretationown dataIt is likely that the vast majority of analyzed neurons did express the P301S tau transgene and exhibited accumulation of hyperphosphorylated tau.
“While this does not rule out the possibility that neurons injected with Lucifer yellow had silenced the P301S tau transgene, it does seem likely that the vast majority of analyzed neurons did express the transgene and exhibited accumulation of hyperphosphorylated tau.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationIn a murine model of prion disease, electron microscopy revealed a selective loss of presynaptic compartments in CA3, while postsynaptic dendritic spines remained.
“For instance, in a murine model of prion disease, electron microscopy revealed a selective loss of presynaptic compartments in CA3, while postsynaptic dendritic spines remained (Gray et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gray et al., 2009 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor an animal to be included in statistical analyses for dendritic spine density and morphology, a minimum of 100 μm of dendrite length had to be reconstructed and analyzed.
“For an animal to be included in statistical analyses for dendritic spine density and morphology a minimum of 100 μm of dendrite length had to be reconstructed and analyzed; thus, there were instances where an animal was not included in the analysis of apical dendrites, but was included in the collective analysis of all dendrites for that animal.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSeparate standard curves were generated for the modified ELISA incubation times.
“Separate standard curves were generated for the modified incubation times.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenImaging was performed by a blinded experimenter.
“Imaging was performed by a blinded experimenter on a Nikon (Tokyo, Japan) Ti2 C2 confocal microscope, using a Plan Apo 60X/1.40 NA oil-immersion objective.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe ELISAs used are specific for human tau and do not measure endogenous murine tau, as indicated by the absence of signal in NTG samples.
“The ELISAs are specific for human tau and do not measure endogenous murine tau, as indicated by the absence of signal in the NTG samples (Fig. 5, C-F).”
Quote in the paperSubstantial claim
The paper relies on this without support.
Synaptosome fractions isolated from hippocampus and PFC represent synaptic compartments.
“To assess synaptic human tau levels, synaptosome fractions were isolated from the PFC of 6 and 9 month old PS19 mice.”
“Soluble whole homogenate and insoluble fractions were isolated from the same hippocampal tissue samples during the synaptosome fractionation process.”
The paper relies on this without support.
The methods used can detect total human tau and tau phosphorylated at S199, T231, and S396 with sufficient sensitivity to reveal differences if present.
“There were no measurable differences in levels of tau phosphorylated at S199, T231, or S396 in synaptosomes or insoluble fractions from PS19 mice at 6 months and 9 months of age by the methods employed herein.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Discussion claims synaptic hyperphosphorylated tau accumulated despite unchanged measured phospho-tau levels
MajorThe discussion attributes the hippocampal spine change to accumulation of hyperphosphorylated tau in synaptosomes, but the results report an increase only in total human tau; all three measured phosphorylated forms remained similar between ages.
“The present study revealed that accumulation of hyperphosphorylated human tau in synaptosomes corresponded with an increase in mean dendritic spine head diameter with age in the hippocampus of PS19 mice.”
“However, levels of human tau phosphorylated at S199, T231, or S396 in synaptosomes were similar at 6 and 9 months (Fig. 6, B-D).”
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Williams, C., Mehrian Shai, R., Wu, Y., Hsu, Y.-H., Sitzer, T., Spann, B., McCleary, C., Mo, Y., & Miller, C. A. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004936 · Cited by 116 · see citing works
Biochemical Fractionation of Brain Tissue for Studies of Receptor Distribution and Trafficking
Hallett, P. J., Collins, T. L., Standaert, D. G., & Dunah, A. W. (2008) · Current Protocols in Neuroscience · doi:10.1002/0471142301.ns0116s42 · Cited by 92 · see citing works
Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid
Henderson, B. W., Greathouse, K. M., Ramdas, R., Walker, C. K., Rao, T. C., Bach, S. V., Curtis, K. A., Day, J. J., Mattheyses, A. L., & Herskowitz, J. H. (2019) · Science Signaling · doi:10.1126/scisignal.aaw9318 · Cited by 92 · see citing works
Self-citationBoros, B. D., Greathouse, K. M., Gearing, M., & Herskowitz, J. H. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.09.003 · Cited by 90 · see citing works
Self-citationShahani, N., Subramaniam, S., Wolf, T., Tackenberg, C., & Brandt, R. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4245-05.2006 · Cited by 81 · see citing works
Gray, B. C., Siskova, Z., Perry, V. H., & O'Connor, V. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.04.001 · Cited by 78 · see citing works
In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy
Crescenzi, R., DeBrosse, C., Nanga, R. P. R., Reddy, S., Haris, M., Hariharan, H., Iba, M., Lee, V. M. Y., Detre, J. A., Borthakur, A., et al. (2014) · NeuroImage · doi:10.1016/j.neuroimage.2014.06.067 · Cited by 73 · see citing works
Briggs, D. I., Defensor, E., Memar Ardestani, P., Yi, B., Halpain, M., Seabrook, G., & Shamloo, M. (2017) · eneuro · doi:10.1523/eneuro.0025-17.2017 · Cited by 61 · see citing works
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Efimova, N., Korobova, F., Stankewich, M. C., Moberly, A. H., Stolz, D. B., Wang, J., Kashina, A., Ma, M., & Svitkina, T. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3520-16.2017 · Cited by 50 · see citing works
Actin Tyrosine-53-Phosphorylation in Neuronal Maturation and Synaptic Plasticity
Bertling, E., Englund, J., Minkeviciene, R., Koskinen, M., Segerstråle, M., Ċastrén, E., Taira, T., & Hotulainen, P. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.2649-15.2016 · Cited by 44 · see citing works
Greathouse, K. M., Boros, B. D., Deslauriers, J. F., Henderson, B. W., Curtis, K. A., Gentry, E. G., & Herskowitz, J. H. (2018) · Brain Structure and Function · doi:10.1007/s00429-018-1748-4 · Cited by 38 · see citing works
Self-citationBertling, E., & Hotulainen, P. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.05.002 · Cited by 28 · see citing works
Flagged first, then by citations
2 of the 54 references couldn’t be matched to a known paper.
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Terminal complement pathway activation drives synaptic loss in Alzheimer’s disease models
Carpanini, S. M., Torvell, M., Bevan, R. J., Byrne, R. A. J., Daskoulidou, N., Saito, T., Saido, T. C., Taylor, P. R., Hughes, T. R., Zelek, W. M., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01404-w · Cited by 95 · see citing works
Mechanistic insights and emerging therapeutic stratagems for Alzheimer’s disease
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Cadherin-13 Maintains Retinotectal Synapses via Transneuronal Interactions
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System-Level Analysis of Alzheimer’s Disease Prioritizes Candidate Genes for Neurodegeneration
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Dendritic spine head diameter predicts episodic memory performance in older adults
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NRN1 as a therapeutic target for Alzheimer's disease
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Synaptic Organization of Surface AMPARs Changes by Brain Region and TauopathyPreprint
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Synaptic Organization of Surface AMPARs Changes by Brain Region and TauopathyPreprint
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Synaptic Organization of Surface AMPARs Changes by Brain Region and TauopathyPreprint
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- Authors
- Walker, C. K., Greathouse, K. M., Boros, B. D., Poovey, E. H., Clearman, K. R., Ramdas, R., Muhammad, H. M., & Herskowitz, J. H.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Herskowitz, Jeremy H.
- ORCID
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 455
- Pages
- 195-211
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC8142378
- OpenAlex
- W3113300735
- Semantic Scholar
- 19ee93841af56be9d3bf62bb3a612284af0533e6
- Cited by
- 27
- References
- 54
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 2
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (T32 NS061788, NIA F31 AG067635, NIA AG061800, NIA AG054719, NIA AG063755)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- dendritic spine remodeling, hyperphosphorylated tau, tauopathy, Alzheimer's disease, neurofibrillary tangles, CA1 pyramidal neurons, medial prefrontal cortex, dendritic spine density, dendritic spine morphology
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Mice, Transgenic, tau Proteins, Tauopathies, Dendritic Spines, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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