The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease

In the paper

“In turn, the size of the postsynaptic density is correlated with the number of presynaptic vesicles, the number of postsynaptic receptors and the ready-releasable pool of transmitter (Harris and Stevens, 1989; Nusser et al., 1998; Schikorski and Stevens, 1999, 2001; Arellano et al., 2007a).”

What the sources say

• Partly supported

  The Serial electron microscopy section reports that PSD area is proportional to the number of vesicles in the presynaptic axonal varicosity. The Relationships between hippocampal spine geometry and synaptic efficacy section infers that larger PSDs likely contain more receptors, but does not count them. Neither section establishes a correlation with the readily releasable transmitter pool. Page numbers are not available in the indexed passages. (LLM, conf=0.88)

  cites Harris and Stevens, 1989 sourceExperimental — accuracy not yet measured
• Partly supported

  The Figure 4 description reports a positive correlation between synapse size and AMPA-receptor immunolabeling in hippocampal synapses. The paper does not establish that postsynaptic density size correlates with presynaptic vesicle number or the readily releasable transmitter pool; its introductory mention of pool size concerns variability, not that correlation. (LLM, conf=0.87)

  cites Nusser et al., 1998 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Schikorski and Stevens, 1999, 2001

In the paper

“Previous studies in animal models of Alzheimer’s disease have shown that amyloid-β plaques induce local morphological alterations to the dendrites in contact with amyloid-β (Tsai et al., 2004; Spires et al., 2005; Knafo et al., 2009a, b; Merino-Serrais et al., 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites Tsai et al., 2004 source
• Supported

  The Results report that dendrites near plaques became more curved and that dendritic spine density fell most sharply near plaque edges. The Discussion describes a marked change in dendritic structure centered on plaques in the APP transgenic mice, supporting the claimed local morphological alterations. (LLM, conf=0.90)

  cites Spires et al., 2005 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Knafo et al., 2009a, b

In the paper

“In the brain, abnormal phosphorylation of the microtubule-associated protein tau leads to the formation of paired helical filaments (PHFs), the main components of intraneuronal neurofibrillary tangles (Grundke-Iqbal et al., 1986).”

What the sources say

• Partly supported

  The Abstract says the findings suggest that abnormally phosphorylated tau is a component of paired helical filaments (PHFs), and identifies neurofibrillary tangles as a major location of PHFs. It does not establish the stronger causal claim that abnormal phosphorylation leads to PHF formation. (LLM, conf=0.86)

  cites Grundke-Iqbal et al., 1986 sourceExperimental — accuracy not yet measured

In the paper

“Moreover, the length of the spine neck is proportional to the extent of biochemical and electrical isolation of the spine from its parent dendrite (Majewska et al., 2000a, b; Araya et al., 2006).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Majewska et al., 2000a, b
• Partly supported

  The opening section (page unavailable) says biochemical compartmentalization occurs at spine heads because the neck creates a diffusional bottleneck. It also reports that electrical attenuation increases with neck length. It does not establish that the extent of biochemical isolation is proportional to neck length. (LLM, conf=0.87)

  cites Araya et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

“whereas the spine head volume is correlated with the area of the postsynaptic density.”

What the sources say

• Supported

  The Serial electron microscopy section explicitly reports that PSD area was positively correlated with spine head volume. The Discussion also states that spine head dimensions are proportional to PSD area. (LLM, conf=0.95)

  cites Harris and Stevens, 1989 source
• ?Could not verify

  The Figure 2 caption describes a large synapse on a spine and other synapses on smaller spines, but does not establish a correlation between spine-head volume and postsynaptic-density area. Searches for that correlation and for spine volume versus synaptic area found no passage in our copy that states it; page numbers were unavailable. (LLM, conf=0.70)

  cites Nusser et al., 1998 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Schikorski and Stevens, 1999, 2001

In the paper

“Second, pyramidal cells in different cortical regions have considerably distinct structures (Elston et al., 2001; Jacobs et al., 2001) and the data obtained in one region cannot necessarily be applied to another.”

What the sources say

• Supported

  The Discussion states that pyramidal cell morphology varies markedly between cortical regions, including within human cortex. That regional variation supports the caution that structural data from one region cannot necessarily be applied to another. (LLM, conf=0.91)

  cites Elston et al., 2001 source
• ?Not checked — no full text of the sourcecites Jacobs et al., 2001 source

In the paper

“In addition, the course such diseases take is highly variable as the neuropathological changes are not homogenous, neither among patients nor in different regions of the brain of the same patient, giving rise to variation in the alterations to cortical circuits (Garcia-Marin et al., 2009; Blazquez-Llorca et al., 2010).”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Garcia-Marin et al., 2009 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Blazquez-Llorca et al., 2010

In the paper

“Studies on the European ground squirrel demonstrated that PHF-like phosphorylation is induced in the brain during the hibernation of these animals (Arendt et al., 2003), which is similar to the characteristic increase in tau phosphorylation (Avila et al., 2004).”

What the sources say

• Supported

  The Animals section identifies the study subjects as European ground squirrels. The section “Hibernation induces PHF-like phosphorylation of tau” reports enhanced detection of six PHF-like tau phosphoepitopes in cortical and hippocampal extracts during torpor. (LLM, conf=0.94)

  cites Arendt et al., 2003 source

In the paper

“Additionally, the volume of the dendritic spine head is related to the size of the postsynaptic density (Harris and Stevens, 1989; Schikorski and Stevens, 1997; Arellano et al., 2007b), the number of presynaptic vesicles, and the number of vesicles adjacent to the presynaptic cleft (Harris and Stevens, 1989).”

What the sources say

• Partly supported

  The Serial electron microscopy section reports that spine head volume correlates with postsynaptic density area and with the total number of vesicles in the presynaptic axonal varicosity. It says all vesicles in those varicosities were counted, but does not report a separate relationship for vesicles adjacent to the synaptic cleft. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites Harris and Stevens, 1989 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Analysis section says the authors measured spine-head volumes and PSD areas, but does not report a relationship between them. Figure 3 (Appendix; page unavailable) reports a correlation between active-zone size and PSD size instead. The presynaptic-vesicle clauses are cited to Harris and Stevens (1989), not to this paper. (LLM, conf=0.72)

  cites Schikorski and Stevens, 1997 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Arellano et al., 2007b

In the paper

“Moreover, the proximal and distal segments of basal dendrites have different characteristics with respect to integration and synaptic plasticity (Markram et al., 1997; Hausser and Mel, 2003; Gordon et al., 2006; Gelfo et al., 2009; Branco and Häusser, 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites Markram et al., 1997 source
• ?Not checked — no full text of the sourcecites Hausser and Mel, 2003 source
• Supported

  The Discussion describes proximal and distal basal dendrites as distinct plasticity compartments: proximal inputs respond to conventional pairing, whereas distal inputs require NMDA spikes combined with BDNF for LTP. The section on spike timing-dependent plasticity also reports that synaptically evoked NMDA spikes were difficult to obtain proximally, consistent with different local integration properties. No page numbers are supplied in our copy. (LLM, conf=0.90)

  cites Gordon et al., 2006 source

In the paper

“At the cellular level, abnormal tau phosphorylation and the formation of tangles are major events in neuronal degeneration in Alzheimer’s disease (Grundke-Iqbal et al., 1986).”

What the sources say

• Partly supported

  The Abstract (p. 4913) identifies neurofibrillary tangles in Alzheimer disease brain and suggests that tau in paired-helical filaments is abnormally phosphorylated. It does not establish that tangle formation and tau phosphorylation are major events in neuronal degeneration. (LLM, conf=0.84)

  cites Grundke-Iqbal et al., 1986 sourceExperimental — accuracy not yet measured

In the paper

“Indeed, the vast majority of PHF-tauPHF-1-ir neurons had a large amount of aggregated tau, consistent with the hypothesis that PHF-tauAT8 mostly labels the initial stages of a neurofibrillar pathology, while PHF-tauPHF-1 recognizes the later stages (Blazquez-Llorca et al., 2011).”

What the sources say

• Supported

  The “Evolution of the alterations to the tau protein and of the labeling of thorny excrescences” section (page not supplied) says AT8 staining is mostly associated with pre-tangle neurons and PHF-1 with neurons bearing tangles. It presents this ordering as a suggestion and cautions that the patterns may not be sequential within individual neurons, consistent with the citing sentence’s description of a hypothesis. (LLM, conf=0.93)

  cites Blazquez-Llorca et al., 2011 source

In the paper

“However, neurofibrillary tangles appear to be toxic since they are associated with impaired axonal transport, which provokes cell death (Stamer et al., 2002; Terwel et al., 2002; Cente et al., 2006; Smith et al., 2007).”

What the sources say

• Partly supported

  The Discussion (page not provided) links elevated tau to impaired intracellular transport and suggests that resulting traffic jams may speed degeneration. It does not show that neurofibrillary tangles cause the transport defect or that the defect provokes cell death; it notes transport defects even when tau aggregates are absent or minor. (LLM, conf=0.86)

  cites Stamer et al., 2002 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Terwel et al., 2002 source
• ?Not checked — no full text of the sourcecites Cente et al., 2006 source

In the paper

“This interpretation is also supported by a large number of researchers who study dendritic spine alterations both in humans and animal models (see Penzes et al., 2011; Spires-Jones and Knafo, 2012 for recent reviews).”

What the sources say

• Supported

  The Abstract identifies this paper as a review of human postmortem studies and animal studies of dendritic spine alterations. Its Neuropathological studies and Animal models sections discuss evidence from both humans and animal models, supporting the citation's use as a recent review. The citing sentence does not specify what “this interpretation” is, so its substance cannot be assessed here. (LLM, conf=0.88)

  cites Penzes et al., 2011 source
• Supported

  The Introduction identifies this paper as a review of dendritic spine changes in Alzheimer’s disease models. Section 2 discusses spine loss reported in several mouse models and compares it with synapse loss in human Alzheimer’s disease. The citation identifies a relevant recent review; the citing authors’ unspecified “interpretation” is not itself attributed to this source. (LLM, conf=0.89)

  cites Spires-Jones and Knafo, 2012 source

In the paper

“In the CA1 region, the total neuron density was 15 786 in Patient P9, 11 916 in Patient P13 and 12 193 in Patient P14 (neurons/mm3), and the percentage of phospho-tau neurons varied between these patients (Fig. 2 and Supplementary material).”

In the paper

“In the parahippocampal cortex from Patient P9, all the Lucifer yellow-injected neurons analysed that were PHF-tau+ were considered to be Pattern I, whereas in the CA1 from Patients P9, P13 and P14, all the Lucifer yellow-injected neurons analysed that were PHF-tau+ were Pattern IIa.”

In the paper

“However, there were significant differences in the frequency distribution of the volume of dendritic spines for all cases, whereby small dendritic spines were more frequent in PHF-tau+ neurons than in PHF-tau− neurons (Fig. 8L, O and R).”

In the paper

“In Patient P9, the total neuron density in the parahippocampal cortex was 19 560 neurons/mm3, whereas the density of PHF-tauAT8-ir and PHF-tauPHF-1-ir neurons was 2917 and 499 neurons/mm3, respectively (Fig. 2), 15% and 2.5% of the total neuronal density, respectively.”

In the paper

“All Lucifer yellow-injected neurons that were PHF-tauAT8-ir were also PHF-tauPHF-1, whereas some Lucifer yellow-injected neurons that were non-immunostained for PHF-tauAT8 were also labelled for PHF-tauPHF-1 (Supplementary Fig. 5).”

In the paper

“In the present study, we further subdivided Pattern II into Patterns IIa and IIb, depending on the extent of neurofibrillary tangle development visualized with PHF-tauAT8, PHF-tauPHF-1 and thioflavin S (Pattern IIa, intermediate/advanced stages; Pattern IIb, extreme stage: Fig. 3).”

In the paper

“The average dendritic spine length decreased significantly in Patient P9 (14%, Fig. 8B), whereas no differences were found in Patients P13 and P14 (Fig. 8E and H; Supplementary Table 2).”

In the paper

“The frequency distribution revealed a higher frequency of shorter dendritic spines in PHF-tau+ neurons from Patients P9 and P13 (Fig. 8C and F), whereas in Patient P14 short dendritic spines were less frequent on PHF-tau+ neurons than PHF-tau− neurons (Fig. 8I).”

In the paper

“By contrast, in Patients P13 and P14 we found statistical differences between PHF-tau− and PHF-tau+ neurons in the medial/distal portions (Fig. 7C and E), and similar results were found when the data are presented as the average (Fig. 7D and F; Supplementary Table 2).”

In the paper

“However, when PHF-tau+ neurons that had well developed neurofibrillary tangles (Pattern IIb) were injected, these neurons had a reduced dendritic arbor and few or virtually no dendritic spines. The dendritic diameter was also remarkably thin in all these cases (Fig. 6).”

In the paper

“Our results indicate that neurons with advanced neurofibrillary tangles display a remarkable loss of dendritic spines, which is consistent with other studies.”

In the paper

“Importantly, the density of CA3 neurons in Patient P9 was 14 350 neurons/mm3, whereas there were only 8916 neurons/mm3 and 8447 neurons/mm3 in Patients P13 and P14, respectively (Supplementary material), suggesting that the CA3 region in the latter two patients is more pathologically affected than that of Patient P9.”

In the paper

“As summarized in Fig. 9, no changes were found in the number, length or volume of the dendritic spines in neurons with Pattern I, nor in dendrite diameter, whereas several significant alterations were found in neurons showing Pattern II.”

In the paper

“The dendritic spines on pyramidal cells are the main postsynaptic target of excitatory synapses in the cerebral cortex and thus, pyramidal cells are considered the principal building blocks of this structure (DeFelipe and Fariñas, 1992).”

What the sources say

• ?Not checked — no full text of the sourcecites DeFelipe and Fariñas, 1992 source

In the paper

“Nevertheless, it is important to mention that both PHF-tauAT8 and PHF-tauPHF-1 antibodies were produced in mouse. Thus, the labeling of neurons for both PHF-tauAT8 PHF-tauPHF-1 could be due to antibody cross-reactivity.”

In the paper

“Another method involving intracellular injections of marker substances in fixed brain tissue is currently considered the best approach to visualize the dendritic spines in the human brain and is a well-established technique (Einstein, 1988; Buhl et al., 1990).”

What the sources say

• ?Not checked — no full text of the sourcecites Einstein, 1988 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Buhl et al., 1990

In the paper

“This result is suggestive of a local toxic effect, since the density of dendritic spines in the pre-terminal dendritic segment was similar to that found in dendrites lacking PHF-tauAT8.”

In the paper

“In addition, it is not possible to know which neurons have developed a neurofibrillar pathology before injection and hence, the proportion of cells showing a neurofibrillar pathology is rather unpredictable.”

In the paper

“Third, the morphological alterations observed in human pathological tissue are very difficult to interpret due to the high interindividual variability (sex, age, medical treatment, etc.), factors that could affect brain structure.”

In the paper

“Neurons with Pattern II typically form neurofibrillary tangles (tangle stage).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Blazquez-Llorca et al., 2010

In the paper

“Finally, Lucifer yellow-injected neurons with Pattern IIb (with well-developed neurofibrillary tangles) had a relatively small dendritic tree, with thin dendrites and very few or no spines, which may simply be due to a more advanced stage of atrophy.”

In the paper

“Furthermore, changes in the denervation/reinnervation of CA3 pyramidal neurons by mossy fibres were also found during hibernation/arousal (Popov and Bocharova, 1992) and they were associated with a reversible PHF-like phosphorylation of tau over a similar time course.”

What the sources say

• ?Not checked — no full text of the sourcecites Popov and Bocharova, 1992 source

In the paper

“For example, the synaptic connections of axons that arise within the same cortical column in the neocortex preferentially innervate the proximal basal dendrites of pyramidal cells (Markram et al., 1997; Feldmeyer et al., 2002).”

What the sources say

• ?Not checked — no full text of the sourcecites Markram et al., 1997 source
• ?Not checked — no full text of the sourcecites Feldmeyer et al., 2002 source

In the paper

“These observations suggest that neurons in a putative pre-tangle stage or with neurofibrillary tangles in intermediate stages may not be affected (or they may be only slightly affected) or they may be in a reversible state.”

In the paper

“In animal models, changes in the neck length of dendritic spines affects the temporal compartmentalization of calcium and other second messengers, changes that may affect the induction of long-term potentiation (Yuste, 2010; Bloodgood and Sabatini, 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Yuste, 2010 source
• ?Not checked — no full text of the sourcecites Bloodgood and Sabatini, 2005 source

In the paper

“This may be a suitable marker for the initial steps of degeneration, as increased tau aggregation can subsequently be found in some neurons and it can be readily visualized with the PHF-1 tau antibody (PHF-tauPHF-1).”

In the paper

“These observations suggest that cellulipetal disconnection may occur and that the functional consequences of such a process are likely to be selective and progressive in the cerebral cortex as a whole, at least at the cellular level.”

In the paper

“This is not only evident for the proximal, intermediate and distal dendrites of pyramidal neurons in the hippocampus, where neurons in all cornu ammonis fields establish different types of synaptic contacts in each strata that they traverse (Andersen et al., 2007), but it may also occur in other cortical regions.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Andersen et al., 2007

In the paper

“Therefore, the morphology of a dendritic spine determines its synaptic strength and learning rules.”

In the paper

“This is not only evident for the proximal, intermediate and distal dendrites of pyramidal neurons in the hippocampus, where neurons in all cornu ammonis fields establish different types of synaptic contacts in each strata that they traverse (Andersen et al., 2007), but it may also occur in other cortical regions.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Andersen et al., 2007

In the paper

“This sequential loss of dendritic spines appears to be distinct to that found in the presence of amyloid-β plaques, where the dendritic regions close to the extracellular plaques are depleted of dendritic spines irrespective of whether they are proximal or distal to the soma (Knafo et al., 2009a).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Knafo et al., 2009a

In the paper

“Such variation could reflect different steps in the process of neuronal degeneration.”