Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons

May combine two claims.

iPSC-derived neurons or NGN2-induced neurons have been unable to produce the 4R Tau isoform found in adult human brains; only the fetal 0N3R splicing isoform is produced, even after one year of differentiation.

“One of the significant hurdles in modeling AD with iPSC-derived neurons or NGN2-induced neurons for the past decade has been their inability to produce the 4R Tau isoform found in adult human brains [19–22]; only the fetal 0N3R splicing isoform is produced, even after one year of differentiation [19].”

• cites [19] Sposito T, Preza E, Mahoney CJ, Seto-Salvia N, Ryan NS, Morris HR, et al. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet. 2015;24:5260–9. sourceDisputed

  The Results section (‘Postnatal tau splicing is observed at extended time points in vitro’) supports fetal 0N3R-only expression through 100 days, but directly contradicts the claim that it persists after one year: control iPSC-derived neurons expressed 4R tau at day 365. The paper does not report results for NGN2-induced neurons. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [20] Ehrlich M, Hallmann AL, Reinhardt P, Arauzo-Bravo MJ, Korr S, Ropke A, et al. Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein. Stem Cell Reports. 2015;5:83–96. sourceDisputed

  In Results (‘Altered Expression of TAU in FTDP-17 iPSC-Derived Neurons’; page unavailable), the paper reports 4R TAU transcripts in iPSC-derived neurons, including controls, and higher levels in neurons carrying the N279K mutation. It reports predominant fetal TAU protein, not exclusive production of the fetal 0N3R isoform. The paper does not establish the claim about one year of differentiation or NGN2-induced neurons. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [21] Verheyen A, Diels A, Dijkmans J, Oyelami T, Meneghello G, Mertens L, et al. Using human iPSC-derived neurons to model TAU aggregation. PLoS One. 2015;10:e0146127. sourcePartly supported

  The Results report that control iPSC-derived cortical neurons expressed only embryonic 0N3R TAU around day 90, and the Discussion says 4R TAU was undetectable after more than 90 days. The paper does not establish that this persists after one year or address NGN2-induced neurons; its Discussion instead notes reports of mature TAU isoforms after extended culture. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [22] Sato C, Barthelemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, et al. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. 2018;97:1284–98.e7. sourceDisputed

  The Results section reports detectable 4R tau in iPSC-derived neurons matured for six weeks, although 3R predominated. The Discussion likewise states that these neurons expressed much less 4R than 3R—not that they produced only 0N3R tau. The paper does not report a one-year differentiation experiment or a finding about NGN2-induced neurons; page numbers are not available in our copy. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

GSK3β expression is increased in AD.

“To examine whether increased expression of GSK3β in AD [33] is connected to SGK1”

• cites [33] Leroy K, Yilmaz Z, Brion JP. Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol. 2007;33:43–55. sourceDisputed

  The Results section reports that total GSK-3β levels were not significantly different between AD cases and controls; only the active pTyr216 form increased significantly. The Discussion explicitly says total GSK-3β levels were not increased in AD, contrary to the unqualified claim of increased GSK-3β expression. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Hyperphosphorylation of Tau is linked to synaptic dysfunctions and subsequent neurodegeneration in AD.

“Hyperphosphorylation of Tau is linked to synaptic dysfunctions and subsequent neurodegeneration in AD [9].”

• cites [9] Chang CW, Shao E, Mucke L. Tau: enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies. Science. 2021;371:eabb8255. sourcePartly supported

  The “Pathogenic mechanisms of abnormal tau” section (page not supplied) says acetylated, hyperphosphorylated FTLD-tau may contribute to neural dysfunction. It does not establish that tau hyperphosphorylation leads from synaptic dysfunction to neurodegeneration in AD; it also cautions that hyperphosphorylation can be pathogenic or protective depending on the sites involved. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

GSK650394 and EMD638683 decrease activated SGK1 (pSGK1) in AD neurons, while control neurons have a lower pSGK1 level that is also decreased by these inhibitors.

“Western blotting of pSGK1, which recognizes activated SGK1 [28], confirmed the inhibition of activated SGK1 in AD neurons by GSK (100 nM) and EMD (6 µM). In contrast, control neurons had a much lower level of pSGK1 that was also decreased by GSK and EMD (Fig. 3d).”

• cites [28] Hochstetler A, Smith H, Reed M, Hulme L, Territo P, Bedwell A, et al. Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models. Fluids Barriers CNS. 2023;20:61. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Tau hyperphosphorylation increases Tau's propensity to form aggregates.

“and increases its propensity to form aggregates [6].”

• cites [6] Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA. 1994;91:5562–6. sourceCould not verify

  The available Abstract reports that abnormally phosphorylated tau binds normal tau and inhibits microtubule assembly, but it does not say phosphorylation increases tau aggregate formation. Searches for aggregation and self-association found only reference titles, not a finding in this paper; the article’s main text is not available as searchable text in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Intracellular aggregates of hyperphosphorylated Tau correlate with cognitive decline in Alzheimer's disease.

“One of the pathological hallmarks of Alzheimer’s disease is the intracellular aggregates of hyperphosphorylated Tau, which show good correlation to cognitive decline [1, 2].”

• cites [1] Bejanin A, Schonhaut DR, La Joie R, Kramer JH, Baker SL, Sosa N, et al. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain. 2017;140:3286–300. sourceSupported
• cites [2] Boccalini C, Ribaldi F, Hristovska I, Arnone A, Peretti DE, Mu L, et al. The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive decline. Alzheimers Dement. 2024;20:221–33. sourcePartly supported

  The Background identifies neurofibrillary tangles as the tau biomarker, and the Discussion reports that neocortical tau predicted longitudinal cognitive decline. However, the paper assesses tau deposition with PET; our copy does not directly establish that the intracellular aggregates of hyperphosphorylated tau, specifically, were what correlated with decline. The indexed passages have no page numbers. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

SGK1 phosphorylates HDAC4 to regulate epigenetic control in the transcription of many genes.

“SGK1 also phosphorylates HDAC4 to regulate epigenetic control in the transcription of many genes [52].”

• cites [52] Zhang MB, Chen JL, Lu JH, Jia GL, Cao H, Li J. SGK1-HDAC4-HMGB1 signaling pathway in the spinal cord dorsal horn participates in diabetic neuropathic pain. Mol Pain. 2025;21:17448069251321143. sourcePartly supported

  The Introduction says SGK1 acts through HDAC4 phosphorylation and that HDAC4’s resulting movement between the nucleus and cytoplasm is a mechanism regulating gene transcription. The Discussion links HDAC4-associated epigenetic modification to altered HMGB1 expression, but does not establish that this SGK1–HDAC4 pathway controls transcription of many genes. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Acetylated tubulin (AcTub) is a marker for stable microtubules.

“acetylated tubulin (AcTub) (Fig. 5a), a marker for stable microtubules [29]”

• cites [29] Piperno G, LeDizet M, Chang XJ. Microtubules containing acetylated alpha-tubulin in mammalian cells in culture. J Cell Biol. 1987;104:289–302. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

HDAC6 expression is increased in the cortex and hippocampus of AD patients.

“Expression of HDAC6 is increased in the cortex and hippocampus of AD patients [34–36].”

• cites [34] Ding H, Dolan PJ, Johnson GV. Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem. 2008;106:2119–30. sourceSupported
• cites [35] Odagiri S, Tanji K, Mori F, Miki Y, Kakita A, Takahashi H, et al. Brain expression level and activity of HDAC6 protein in neurodegenerative dementia. Biochem Biophys Res Commun. 2013;430:394–9. sourceNot checked — no full text of the source
• cites [36] Zhang L, Sheng S, Qin C. The role of HDAC6 in Alzheimer’s disease. J Alzheimers Dis. 2013;33:283–95. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

By phosphorylating the ubiquitin ligase NEDD4-2, SGK1 regulates the cell surface expression of ENaC channels.

“By phosphorylating the ubiquitin ligase NEDD4-2, SGK1 regulates the cell surface expression of ENaC channels [53].”

• cites [53] Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, et al. Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J. 2001;20:7052–9. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Increased Tau acetylation reduces Tau phosphorylation.

“while increased Tau acetylation reduces Tau phosphorylation [34, 42].”

• cites [34] Ding H, Dolan PJ, Johnson GV. Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem. 2008;106:2119–30. sourcePartly supported

  The Results report that HDAC6 inhibition reduced tau phosphorylation at T231 in cell-culture models, but not at all sites tested (page not provided). The Discussion describes acetylation of α-tubulin as a possible indirect mechanism; it does not show that increased acetylation of tau caused the reduction. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [42] Carlomagno Y, Chung DC, Yue M, Castanedes-Casey M, Madden BJ, Dunmore J, et al. An acetylation-phosphorylation switch that regulates tau aggregation propensity and function. J Biol Chem. 2017;292:15277–86. sourcePartly supported

  The Discussion reports that acetylation of tau at Lys-321 inhibits phosphorylation at Ser-324. The citing sentence omits those site-specific limits and implies that increased tau acetylation reduces tau phosphorylation generally, which this paper does not establish. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

HDAC6 is a tubulin deacetylase and the main tubulin deacetylase.

“HDAC6, a tubulin deacetylase [24].”

• Also stated in: § Increased expression of HDAC6 in cortical neurons derived from AD patients · plain

  “As HDAC6 is the main tubulin deacetylase [31, 32]”

• cites [24] Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417:455–8. sourceNot checked — no full text of the source
• cites [31] Matsuyama A, Shimazu T, Sumida Y, Saito A, Yoshimatsu Y, Seigneurin-Berny D, et al. In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J. 2002;21:6820–31. sourceSupported
• cites [32] Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, et al. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol. 2008;28:1688–701. sourceSupported

May combine two claims.

SGK1 expression is increased in P301S Tau transgenic mice and in postmortem brain tissue from AD patients.

“RNA sequencing (RNAseq) of the prefrontal cortex (PFC) of the P301S human Tau transgenic mouse model of dementia has identified Serum and Glucocorticoid-regulated Kinase-1 (Sgk1) as one of the top-ranking upregulated genes [10].”

• Also stated in: § Introduction · plain

  “RT-qPCR experiments have confirmed the significantly higher level of SGK1 mRNA in the PFC of AD human postmortem brain tissue [10].”

• Also stated in: § Introduction · plain

  “SGK1 upregulation is observed in neurons from single-cell RNAseq of AD human frontal cortex [11] and neuron-specific RNAseq data from P301S mice [12].”

• cites [10] Cao Q, Wang W, Williams JB, Yang F, Wang ZJ, Yan Z. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease. Sci Adv. 2020;6:eabc8096. sourceSupported
• cites [11] Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570:332–7. sourceCould not verify

  The ‘Single-nucleus RNA-seq profiling’ section describes postmortem human prefrontal-cortex samples, while the differential-expression section reports cell-type-specific changes without identifying SGK1. Searches for SGK1 and P301S found no passage establishing increased SGK1 expression in either AD brain tissue or P301S mice; the copy does not address the specific claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [12] Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 2019;28:2111–23.e6. sourceCould not verify

  The Induction of Brain Complement Expression section reports RNA-seq analysis of cells sorted from TauP301S mouse hippocampus and describes increased complement-gene expression, not Sgk1 expression in prefrontal cortex. The STAR+METHODS passages identify the RNA-seq datasets, but the passages retrieved for Sgk1 and prefrontal-cortex RNA-seq do not establish that Sgk1 was a top-ranking upregulated gene or that it increased in AD brain tissue. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SGK1 phosphorylates FOXO3a, inhibiting its nuclear translocation and transcriptional activity, thereby suppressing apoptosis and promoting cell survival.

“For example, it phosphorylates the transcription factor FOXO3a to inhibit its nuclear translocation and transcriptional activity, thus suppressing apoptosis and promoting cell survival [51].”

• cites [51] Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol. 2001;21:952–65. sourceSupported

May combine two claims.

SGK1 contributes to Tau hyperphosphorylation and microtubule depolymerization.

“thus contributing to Tau hyperphosphorylation and microtubule depolymerization [18].”

• cites [18] Yang YC, Lin CH, Lee EH. Serum- and glucocorticoid-inducible kinase 1 (SGK1) increases neurite formation through microtubule depolymerization by SGK1 and by SGK1 phosphorylation of tau. Mol Cell Biol. 2006;26:8357–70. sourcePartly supported

  The Results (page not provided) show that SGK1 phosphorylates tau at Ser214 and promotes microtubule depolymerization. They do not establish tau hyperphosphorylation: the paper reports that the other tau phosphorylation sites tested remained unchanged. The Discussion (page not provided) also says SGK1 phosphorylation of tau is probably not related to Alzheimer's disease pathogenesis. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

Increased expression of HDAC6 decreases Tau acetylation, a key factor contributing to the formation of Tau aggregates.

“Increased expression of HDAC6 decreases Tau acetylation [40], which is a key factor contributing to the formation of Tau aggregates [39, 49].”

• cites [40] Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:252. sourceSupported
• cites [39] Trzeciakiewicz H, Ajit D, Tseng JH, Chen Y, Ajit A, Tabassum Z, et al. An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline. Nat Commun. 2020;11:5522. sourceSupported
• cites [49] Tseng JH, Xie L, Song S, Xie Y, Allen L, Ajit D, et al. The deacetylase HDAC6 mediates endogenous neuritic Tau pathology. Cell Rep. 2017;20:2169–83. sourcePartly supported

  The Discussion reports that inhibiting HDAC6 mildly increased tau acetylation, which supports a role for HDAC6 activity in regulating it. The paper does not show that increased HDAC6 expression decreases tau acetylation; it also reports increased acetylated tau in HDAC6-containing neuritic beads. Citation [40] is attached to the HDAC6 clause, not the separate aggregation claim. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

Tau hyperphosphorylation triggers the formation of neurofibrillary tangles and is a key pathological hallmark of AD.

“Tau hyperphosphorylation, which triggers the formation of neurofibrillary tangles, is a key pathological hallmark of AD [48].”

• cites [48] Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA. 1986;83:4913–7. sourcePartly supported

  The Abstract links abnormally phosphorylated tau to paired-helical filaments in Alzheimer disease neurofibrillary tangles, supporting its association with AD pathology. It does not show that tau hyperphosphorylation triggers tangle formation; the paper describes that conclusion as evidence suggesting tau is a component of the filaments. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

SGK1 inhibition lowers pTau and rescues deficits in synaptic transmission and memory tests in P301S mice.

“SGK1 inhibition lowers pTau and rescues the deficits in synaptic transmission and memory tests in P301S mice [10].”

• cites [10] Cao Q, Wang W, Williams JB, Yang F, Wang ZJ, Yan Z. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease. Sci Adv. 2020;6:eabc8096. sourceSupported

May combine two claims.

SGK1 overexpression significantly decreases AcTub in control neurons, but not in AD neurons.

“When SGK1 was overexpressed (Figs. 4e, 6a, b), we found a significant decrease in AcTub in control neurons, but not AD neurons, by immunostaining (Fig. 6a, c) (Fig. S8) and Western blotting (Fig. 6d).”

May combine two claims.

SGK1 knockdown significantly increases AcTub in AD neurons, but not in control neurons.

“SGK1 knockdown significantly increased AcTub in AD neurons, but not control neurons (Figs. 6a, c, d, S8).”

May combine two claims.

Lentiviral SGK1 shRNA significantly decreases the high endogenous SGK1 level in AD neurons, but not the low endogenous level in control neurons.

“Conversely, lentivirus expressing SGK1 shRNA significantly decreased the high endogenous SGK1 level in AD neurons, but not the low endogenous level in control neurons (Fig. 4e).”

May combine two claims.

SGK1 knockdown significantly decreases HDAC6 levels in AD neurons, but not appreciably in control neurons.

“SGK1 knockdown significantly decreased HDAC6 levels in AD neurons, but not appreciably in control neurons from their low HDAC6 levels (Figs. 8, S10).”

May combine two claims.

In AD2 neurons, SGK1 inhibitors EMD638683 or GSK650394 dose-dependently decrease SGK1, pTau at AT8 and S214, and HDAC6, and increase acetylated tubulin.

“Interestingly, SGK1 level was decreased by each SGK1 inhibitor in a dose-dependent manner. Consistent with this, pTau levels at AT8 and S214 sites were reduced in parallel. There was a commensurate increase of acetylated tubulin and a corresponding decrease of HDAC6 (Fig. 9a).”

May combine two claims.

SGK1 overexpression significantly increases Tau phosphorylation at S202/T205 (AT8) and S214 in control neurons, but not beyond the already high levels in AD neurons.

“SGK1 overexpression significantly increased Tau phosphorylation on S202/T205 (AT8 sites) and S214 in control neurons, but not beyond the already high levels in AD neurons (Fig. 4a, c).”

May combine two claims.

Microtubule stability is significantly lower in AD-derived cortical neurons, as shown by higher free tubulin in the supernatant and lower polymerized tubulin in the pellet.

“Western blotting showed significantly higher levels of free tubulin in the supernatant fraction (Fig. 5d) and significantly lower levels of polymerized tubulin in the pellet fraction from AD neurons (Fig. 5e).”

May combine two claims.

The GSK3β inhibitor CHIR 99021 (1 μM for 48 h) significantly inhibits activated phospho-GSK3 α and β isoforms and reduces GSK3β expression in AD neurons.

“we treated CT1 and AD1 neurons with the selective GSK3β inhibitor CHIR 99021 (1 µM for 48 h), which significantly inhibited the activated phospho-GSK3 (pGSK) α and β isoforms, and reduced the expression level of GSK3β in AD neurons (Fig. 9b).”

May combine two claims.

SGK1 overexpression significantly increases HDAC6 in control neurons, but not in AD neurons.

“We overexpressed SGK1 and found a significant increase of HDAC6 in control neurons, but not in AD neurons, which already had a high level of HDAC6 (Figs. 8, S10).”

May combine two claims.

Doxycycline-inducible lentiviral SGK1 overexpression significantly increases SGK1 expression in control neurons over its endogenous level, but does not significantly increase SGK1 expression in AD neurons beyond their already high endogenous level.

“Western blotting showed that the doxycycline-inducible lentivirus of SGK1 significantly increased SGK1 expression in control neurons over its endogenous level, but did not significantly increase SGK1 expression in AD neurons beyond its already high endogenous level.”

May combine two claims.

SGK1 knockdown significantly decreases Tau phosphorylation at AT8 and S214 sites in AD neurons, but not in control neurons.

“SGK1 knockdown significantly decreased Tau phosphorylation on these sites in AD neurons, but not in control neurons, where pTau was already low (Fig. 4b, d).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Inhibition of SGK1 also reduces its expression.

“inhibition of SGK1, which also reduced its expression”

May combine two claims.

Lentiviruses expressing M2rtTA or scrambled shRNA had no significant effect on SGK1 expression or pTau, so M2rtTA was used as the transduction control.

“Because lentiviruses expressing the reverse tetracycline transactivator M2rtTA or scrambled shRNA had no significant effect on SGK1 expression or pTau, we used M2rtTA as the transduction control.”

May combine two claims.

Elevated HDAC6 in AD neurons reduces AcTub, which destabilizes microtubules.

“elevated HDAC6 in AD neurons reduced AcTub, which destabilize microtubules”

• AssumptionRests on an assumption: The iPSC-derived cortical neuron phenotypes reflect mechanisms operating in the AD brain.

May combine two claims.

In the AD state, elevated oxidative stress may induce SGK1 to increase pTau, which destabilizes microtubules and attenuates microtubule-dependent transport.

“In the AD state, elevated oxidative stress may induce SGK1 to increase pTau, which destabilizes microtubules and attenuates microtubule-dependent transport.”

• AssumptionRests on an assumption: The iPSC-derived cortical neuron phenotypes reflect mechanisms operating in the AD brain.

Probably not a substantial claim: may not pass S3 (load-bearing).

SGK1 is an immediate early gene induced by a variety of cellular stress.

“SGK1 is an immediate early gene induced by a variety of cellular stress [16].”

• cites [16] Lang F, Bohmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V. Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev. 2006;86:1151–78. sourceNot checked — no full text of the source

May combine two claims.

The increase in SGK1, HDAC6, and pTau, as well as the decrease in AcTub and microtubule stability, appear to be interconnected and may reflect elevated cellular stress in AD.

“Second, the increase in SGK1, HDAC6, and pTau, as well as the decrease in AcTub and microtubule stability appear to be interconnected and may reflect elevated cellular stress in AD.”

• AssumptionRests on an assumption: The iPSC-derived cortical neuron phenotypes reflect mechanisms operating in the AD brain.

Probably not a substantial claim: may not pass S3 (load-bearing).

The use of CF-1 mice to produce mouse embryonic fibroblasts for culturing human iPSCs is approved by the University at Buffalo Institutional Animal Care and Use Committee.

“The use of CF-1 mice to produce mouse embryonic fibroblasts for culturing human iPSCs is approved by the University at Buffalo Institutional Animal Care and Use Committee.”

Probably not a substantial claim: may not pass S3 (load-bearing).

SGK1 exerts a broad and coordinated homeostatic response to maximize cell survival at different conditions.

“As SGK1 appears to exert a broad and coordinated homeostatic response to maximize cell survival at different conditions”

May combine two claims.

Reduced AcTub destabilizes microtubules, which reduces neurotransmission.

“which destabilize microtubules to reduce neurotransmission [47]”

• cites [47] Hirokawa N, Niwa S, Tanaka Y. Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron. 2010;68:610–38. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Increased AcTub stabilizes microtubules and promotes microtubule-based transport.

“Increased AcTub stabilizes microtubules and promotes microtubule-based transport [41]”

• cites [41] Reed NA, Cai D, Blasius TL, Jih GT, Meyhofer E, Gaertig J, et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol. 2006;16:2166–72. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The use of human iPSCs from de-identified commercial sources is not human subject research.

“The use of human iPSCs from de-identified commercial sources is not human subject research.”

Probably not a substantial claim: may not pass S3 (load-bearing).

SGK1 phosphorylates many substrates in different types of cells.

“SGK1 phosphorylates many substrates in different types of cells [16].”

• cites [16] Lang F, Bohmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V. Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev. 2006;86:1151–78. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

All methods used in the study were performed in accordance with guidelines of International Society for Stem Cell Research.

“All methods used in the study were performed in accordance with guidelines of International Society for Stem Cell Research.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All constructs made by us were verified by sequencing.

“All constructs made by us were verified by sequencing.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The intensity of tubulin bands was quantified against actin bands from three different experiments.

“The intensity of tubulin bands was quantified against actin bands from three different experiments with NIH Image J.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

CIRM does not provide specific details on the clinical diagnosis of AD and the presence or absence of family history or disease-causing genetic mutations on these patients.

“CIRM does not provide specific details on the clinical diagnosis of AD and the presence or absence of family history or disease-causing genetic mutations on these patients.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Sample size is based on the observed effect size in preliminary studies.

“Sample size is based on the observed effect size in preliminary studies.”

May combine two claims.

M2rtTA and scrambled control shRNA had no significant effect in the experiments.

“As M2rtTA and scrambled control shRNA had no significant effect in the experiments”

Probably not a substantial claim: may not pass S3 (load-bearing).

All results are from three technical replicates of three independent biological samples for each subject.

“All results are from three technical replicates of three independent biological samples for each subject.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Periodical mycoplasma tests by PCR showed no contamination.

“Periodical mycoplasma tests by PCR showed no contamination.”

Probably not a substantial claim: may not pass S3 (load-bearing).

At least 5 random images were quantified for a line of neurons at each condition.

“At least 5 random images were quantified for a line of neurons at each condition.”