The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation

In the paper

“Notably, the APOE-R136S has severely reduced binding affinity to heparin, as the mutation occurs within the receptor-binding region of APOE36,45,58.”

What the sources say

• Supported

  The Abstract identifies R136S in a region involved in lipoprotein-receptor binding and reports that ApoE3 Christchurch had the lowest heparin-binding ability of the ApoE isoforms compared. This supports the claim of markedly reduced heparin binding, although the passage does not quantify that reduction. (LLM, conf=0.92)

  cites [36] Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). source
• Disputed

  The Discussion (page unavailable) places residue 136 outside the recognized receptor-binding domain, contrary to the citing sentence’s explanation. It reports that APOE-R136S had the same heparin affinity as another APOE2 variant under denaturing conditions; it does not report severely reduced heparin affinity relative to normal APOE. (LLM, conf=0.84)

  Checked by a reasoning model — may be wrong.

  cites [45] Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R. & Carrell, R. W. Apolipoprotein E2-Christchurch (136 Arg–Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J. Clin. Invest. 80, 483–490 (1987). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [58] Lalazar, A. et al. Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions. J. Biol. Chem. 263, 3542–3545 (1988). source

In the paper

“The early p-Tau staining types 1 and 2 were enriched in PS19-E3 mice (Fig. 1h), as seen previously7.”

What the sources say

• Disputed

  The paper’s discussion of p-tau staining patterns (section labeled Abstract; page unavailable) says types 1 and 2 were enriched in TEKO mice, not TE3 mice, and type 4 was enriched in TE4 mice. It describes these patterns in 9-month-old mice; it does not identify types 1 and 2 as early-age staining. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). sourceExperimental — accuracy not yet measured

In the paper

“By contrast, APOE4 has increased binding affinity (up to two-fold) for heparin and HSPG over APOE3 (refs. 32–35).”

What the sources say

• ?Not checked — no full text of the sourcecites [32] Mahley, R. W. & Rall, S. C. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genom. Hum. Genet. 1, 507–537 (2000). source
• Disputed

  In the ‘Metabolism of ¹²⁵I-apoE3- and ¹²⁵I-apoE4-enriched β-VLDL’ section (page unavailable), similar amounts of the two isoforms bound to wild-type CHO cells; the paper reports greater subsequent retention of apoE3. It does not report a two-fold greater apoE4 binding affinity for heparin or HSPG. The cell-binding experiment is not a direct affinity measurement, but its reported comparison runs contrary to the cited claim. (LLM, conf=0.78)

  Checked by a reasoning model — may be wrong.

  cites [33] Ji, Z.-S., Pitas, R. E. & Mahley, R. W. Differential cellular accumulation/retention of apolipoprotein E mediated by cell surface heparan sulfate proteoglycans. Apolipoproteins E3 and E2 greater than E4. J. Biol. Chem. 273, 13452–13460 (1998). sourceExperimental — accuracy not yet measured
• Partly supported

  The surface plasmon resonance passage (indexed as Abstract; page unavailable) gives heparin-binding dissociation constants of 0.15 µM for apoE4 and 0.32 µM for apoE3, consistent with approximately twofold higher affinity for heparin, although the authors describe them as very similar. The cited passages do not establish a corresponding apoE4-versus-apoE3 affinity difference for HSPG. (LLM, conf=0.84)

  cites [34] Libeu, C. P. et al. New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. J. Biol. Chem. 276, 39138–39144 (2001). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable) report that apoE4 showed two- or three-fold higher binding to heparan sulfate (HS) and dermatan sulfate than apoE3. But this study does not establish the claimed increase in affinity for heparin or intact HSPG; it also says equilibrium affinity for HS did not differ much among the lipidated isoforms. The reported binding increase is not limited to two-fold. (LLM, conf=0.90)

  cites [35] Yamauchi, Y. et al. Role of the N- and C-Terminal domains in binding of apolipoprotein E isoforms to heparan sulfate and dermatan sulfate: a surface plasmon resonance study. Biochemistry 47, 6702–6710 (2008). sourceExperimental — accuracy not yet measured

In the paper

“Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD)1–3.”

What the sources say

• Supported

  In “Genetics, Epigenetics, and Epidemiology,” the review calls apoE4 the top late-onset AD gene in GWAS across populations and says other identified genes contribute moderately by comparison. This supports the claim that APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease. (LLM, conf=0.94)

  cites [1] Huang, Y. & Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222 (2012). source
• Partly supported

  The “ApoE and Neuropathology” section calls apoE4 the major known genetic risk factor for Alzheimer’s disease in many populations. It does not specify late-onset disease, and the citing sentence omits the population qualifier. (LLM, conf=0.83)

  cites [2] Mahley, R. W., Weisgraber, K. H. & Huang, Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc. Natl Acad. Sci. USA 103, 5644–5651 (2006). sourceExperimental — accuracy not yet measured
• Supported

  In “Other Lipid Metabolism–Related Genes and AD” (page unavailable), the review contrasts apoE4’s association with AD against the weak associations of other genes it discusses. The “Aβ-Dependent Effects of ApoE4 on AD Pathogenesis” section also describes how apoE4 may contribute to AD. Together, these passages support the citing sentence’s broad characterization of APOE4 as the leading genetic risk factor for late-onset AD. (LLM, conf=0.84)

  cites [3] Huang, Y. & Mahley, R. W. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol. Dis. 72PA, 3–12 (2014). source

In the paper

“It exacerbates AD-related pathologies, including amyloid-beta (Aβ) plaques, Tau tangles, neurodegeneration and neuroinflammation4–16.”

What the sources say

• ?Not checked — no full text of the sourcecites [4] Koutsodendris, N., Nelson, M. R., Rao, A. & Huang, Y. Apolipoprotein E and Alzheimer’s disease: findings, hypotheses, and potential mechanisms. Annu. Rev. Pathol. 17, 73–99 (2022). source
• ?Not checked — no full text of the sourcecites [5] Harris, F. M., Brecht, W. J., Xu, Q., Mahley, R. W. & Huang, Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J. Biol. Chem. 279, 44795–44801 (2004). source
• Partly supported

  The Introduction associates apoE4 with increased amyloid plaques and tau tangles. The Discussion reports increased Aβ production, tau phosphorylation, and GABAergic neuron degeneration in apoE4 cultures. The passages do not address neuroinflammation, so that part of the claim is unsupported by this source. Page numbers were not available in our copy. (LLM, conf=0.87)

  cites [6] Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24, 647–657 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s Abstract reports greater Aβ pathology with ApoE4 and, in P301S tau mice, higher tau levels, markedly greater brain atrophy, and more neuroinflammation. It does not establish that ApoE4 increases Tau tangles specifically; it reports tau redistribution and distinct phosphorylated-tau staining patterns instead. The mouse findings are also not direct evidence for every listed pathology in human AD. (LLM, conf=0.84)

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page not provided) discusses amyloid-beta plaque formation as a proposed APOE4 mechanism and reports neurodegeneration and NFT-like inclusions associated with apoE fragments. The Results section on p-tau-containing inclusions (page not provided) finds more such inclusions in apoE4 than apoE3 mice. The paper does not establish that APOE4 exacerbates amyloid-beta plaques, and the passages found do not address neuroinflammation. (LLM, conf=0.88)

  cites [8] Brecht, W. J. et al. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527–2534 (2004). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (page not provided) reports neurodegeneration and phosphorylated-Tau pathology in mice expressing an apoE4 fragment. The Introduction (page not provided) says apoE4 colocalizes with amyloid plaques and neurofibrillary tangles, but that does not establish that it exacerbates either. The passages do not report exacerbated neuroinflammation. (LLM, conf=0.88)

  cites [9] Andrews-Zwilling, Y. et al. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J. Neurosci. 30, 13707–13717 (2010). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report increased tau phosphorylation and reduced neuronal survival in apoE4 knock-in mouse cultures; the Discussion links apoE4 neurotoxicity to neurodegeneration and describes a pathway to neurofibrillary tangles (page numbers unavailable). The passages do not establish that APOE4 exacerbates amyloid-beta plaques or neuroinflammation, and the study measures tau phosphorylation rather than tangle burden. (LLM, conf=0.88)

  cites [10] Li, G. et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell 5, 634–645 (2009). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says apoE4 significantly exacerbated neurodegeneration in P301S tauopathy mice. The Results link apoE to phosphorylated-tau pathology and show greater microglial activation in apoE4 mice than in apoE-deficient mice. The paper does not show that APOE4 exacerbates amyloid-β plaques, and its tau findings concern tau pathology rather than specifically demonstrating more tangles. (LLM, conf=0.88)

  cites [11] Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546–2561 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that ApoE binds amyloid-beta and is present in senile plaques and neurofibrillary tangles; it also reports an association between APOE-e4 and late-onset familial Alzheimer disease. The passage labeled MATERIALS AND METHODS suggests a possible role for ApoE-E4 but does not establish that this isoform exacerbates those lesions. The cited passages do not support exacerbation of neurodegeneration or neuroinflammation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [12] Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction links APOEε4 to increased amyloid-β burden and reports associations with inflammation and neurodegeneration in mouse models. The Results and Discussion support a stronger relationship between amyloid-β and tau pathology in APOEε4 carriers. The paper does not establish that APOEε4 exacerbates neuroinflammation or neurodegeneration generally; its statement about those outcomes is limited to an association reported in mouse models. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [13] Therriault, J. et al. APOEε4 potentiates the relationship between amyloid-β and tau pathologies. Mol. Psychiatry 26, 5977–5988 (2021). sourceExperimental — accuracy not yet measured

In the paper

“As reported previously6, the E4 neuron culture had a lower fraction of GABA+ inhibitory neurons than the E3 neuron culture (Supplementary Fig. 2c,d).”

What the sources say

• Supported

  The Results section reports significantly fewer GABA-positive neurons in apoE4/4-hiPSC-derived cultures than in apoE3/3-hiPSC-derived cultures. The Online Methods also report a lower GABA-positive percentage in apoE4/4 than apoE3/3 neuronal cultures. Page numbers were not provided in our copy. (LLM, conf=0.93)

  cites [6] Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24, 647–657 (2018). source

In the paper

“The reported patient was protected from the clinical effects of PSEN1-E280A, a highly penetrant mutation causing EOAD dementia41,42, for 28 years by the homozygous APOE3-R136S mutation36.”

What the sources say

• Partly supported

  The case-report text (section labeled Abstract; page unavailable) says the PSEN1 E280A carrier had two copies of APOE3 Christchurch (R136S) and did not develop mild cognitive impairment until her seventies, nearly three decades after the typical onset age. It identifies APOE3ch homozygosity as the most likely genetic modifier, but omits her exact age and acknowledges that other factors could have contributed. Thus, neither precisely 28 years nor protection caused solely by APOE3-R136S is established. (LLM, conf=0.88)

  cites [36] Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). sourceExperimental — accuracy not yet measured
• Supported

  The Abstract identifies PSEN1 E280A carriers in an autosomal dominant Alzheimer disease kindred, and the Discussion reports dementia onset at a mean age of 49 years and says carriers develop Alzheimer disease with virtual certainty. This supports the early-onset, highly penetrant mutation description to which citations 41 and 42 are attached. The separate APOE3-R136S and 28-year protection claim is attached to citation 36, not this source. (LLM, conf=0.91)

  cites [41] Quiroz, Y. T. et al. Association between amyloid and tau accumulation in young adults with autosomal dominant Alzheimer disease. JAMA Neurol. 75, 548–556 (2018). source
• ?Not checked — no full text of the sourcecites [42] Lemere, C. A. et al. The E280A presenilin 1 Alzheimer mutation produces increased Aβ 42 deposition and severe cerebellar pathology. Nat. Med. 2, 1146–1150 (1996). source

In the paper

“Recent findings show that cell surface HSPGs mediate a large portion of neuronal uptake of Tau monomers and aggregates46,57.”

What the sources say

• Partly supported

  The Results (Functional genomics to find modulators of tau uptake; page unavailable) report that knockdown of HSPG-related genes reduced monomer uptake by over 50% and also reduced oligomer uptake; the knockdowns reduced tau uptake in iPS-derived neurons. But the Results (Internalization of tau in CNS culture is regulated by quaternary structure; page unavailable) say intact fibrils were not efficiently internalized, so the unqualified reference to aggregates is broader than the evidence supports. (LLM, conf=0.85)

  cites [46] Rauch, J. N. et al. Tau internalization is regulated by 6-O sulfation on heparan sulfate proteoglycans (HSPGs). Sci. Rep. 8, 6382 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that HSPGs mediate tau aggregate uptake into neurons in vitro and in vivo. The Results distinguish fibrils from monomers, stating that tau repeat-domain fibrils, but not monomers, are readily internalized into neural precursor cells. This source therefore supports the aggregate portion of the claim, but not HSPG-mediated neuronal uptake of tau monomers. (LLM, conf=0.90)

  cites [57] Holmes, B. B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138–E3147 (2013). sourceExperimental — accuracy not yet measured

In the paper

“A major functional effect of the R136S mutation is disruption of its binding to anionic HSPGs on cell surface36,45.”

What the sources say

• Partly supported

  The paper reports that APOE3 Christchurch (R136S) had the lowest heparin-binding ability among the APOE isoforms tested (Abstract; page unavailable). The Methods describe an in vitro heparin-column assay, not a measurement of binding to HSPGs on cell surfaces. Thus, reduced binding is supported, but disruption of cell-surface HSPG binding is not directly established. (LLM, conf=0.85)

  cites [36] Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results identify the Arg136→Ser substitution, and the Discussion says it could alter receptor binding. But the Discussion does not establish disrupted binding to cell-surface HSPGs; its preliminary heparin-affinity comparison was with another APOE2 variant under denaturing conditions. (LLM, conf=0.84)

  cites [45] Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R. & Carrell, R. W. Apolipoprotein E2-Christchurch (136 Arg–Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J. Clin. Invest. 80, 483–490 (1987). sourceExperimental — accuracy not yet measured

In the paper

“Western blotting analysis of cell lysates with PHF1 and AT8 antibodies revealed that the E3 neurons had a significant reduction in p-Tau levels compared to E4 neurons (Fig. 2a,c,d and Supplementary Fig. 3b,c), confirming our previous report6.”

What the sources say

• Supported

  The Results section, “Phosphorylated tau (p-tau) levels are higher in human apoE4/4 neurons than human apoE3/3 neurons,” reports significantly higher p-tau in E4 than E3 neurons by western blot, including with AT8 and PHF1 antibodies. This supports the citing sentence’s attribution that its E3-versus-E4 finding confirms the previous report. (LLM, conf=0.94)

  cites [6] Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24, 647–657 (2018). source

In the paper

“PS19-E4 mice displayed roughly two-fold higher AT8+ p-Tau coverage area than PS19-E3 mice (Fig. 1b,c), as reported previously7,55.”

What the sources say

• Partly supported

  The paper’s main text (Fig. 2b discussion; page unavailable in our copy) reports greater AT8-positive p-tau covered area in the hippocampus of 3-month-old TE4 mice. Extended Data Figure 4 also quantifies AT8-covered area for TE3 and TE4 mice, but the text in our copy does not give values establishing the claimed roughly two-fold difference. (LLM, conf=0.84)

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section ('Removal of APOE4 from neurons drastically reduces tau pathology'; page unavailable) reports that AT8 staining showed significantly more tau pathology throughout the hippocampus in PS19-fE4 mice than in PS19-fE3 mice. Our copy does not state that AT8-positive coverage area was roughly two-fold higher, so the magnitude is not verified. (LLM, conf=0.85)

  cites [55] Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023). sourceExperimental — accuracy not yet measured

In the paper

“A recent discovery that a rare APOE variant, APOE3-R136S (APOE3-Christchurch)36, strongly protects against early-onset Alzheimer’s disease (EOAD)”

What the sources say

• Partly supported

  The Abstract reports that a PSEN1 mutation carrier with two copies of APOE3-Christchurch developed mild cognitive impairment nearly three decades later than expected, supporting a protective association in this case. It does not establish that the variant generally strongly protects against early-onset Alzheimer’s disease: the authors identify it as the best candidate modifier in this subject, acknowledge other possible factors, and suggest that homozygosity may be required. (LLM, conf=0.88)

  cites [36] Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). sourceExperimental — accuracy not yet measured

In the paper

“suggesting that the R136S mutation results in less APOE4 fragmentation6.”

What the sources say

• ?Could not verify

  The Results report less apoE fragmentation after gene editing converted apoE4 to apoE3, but do not identify that change as R136S. Searches for R136S and Arg136Ser found no passage testing or discussing that mutation’s effect on fragmentation. The cited paper therefore does not establish the specific claim. (LLM, conf=0.76)

  cites [6] Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24, 647–657 (2018). sourceExperimental — accuracy not yet measured

In the paper

“suggesting the contribution of microgliosis to hippocampal degeneration, as reported in previous studies7,55”

What the sources say

• Supported

  In the paper’s indexed Abstract (page not specified), the authors report increased microglial activation in ApoE4 tauopathy mice and propose that activated microglia could harm injured neurons and exacerbate neurodegeneration. This supports the citing sentence’s tentative suggestion of a contribution to hippocampal degeneration, rather than establishing microgliosis as a proven cause. (LLM, conf=0.87)

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). source
• Supported

  The Results section ('Gliosis is drastically reduced after removal of neuronal APOE4'; page not supplied) reports a strong negative correlation between microglial coverage and hippocampal volume and describes microglial activation as a potential contributor to hippocampal degeneration. This supports the citing sentence's tentative wording. (LLM, conf=0.92)

  cites [55] Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023). source

In the paper

“In 10-month-old PS19-E4 mice, the AT8 (p-Tau) percent coverage area was negatively correlated with hippocampal volume (Fig. 4f), as shown previously7,55, indicating a deleterious role of p-Tau in hippocampal degeneration.”

What the sources say

• Partly supported

  The paper reports that p-tau staining patterns in 9-month-old tau/ApoE mice correlated with brain atrophy (Abstract; page not specified). It does not report the claimed negative correlation between AT8 percent coverage and hippocampal volume specifically in 10-month-old PS19-E4 mice. (LLM, conf=0.84)

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). sourceExperimental — accuracy not yet measured
• Supported

  The Results section, “Neurodegeneration is reduced after removal of neuronal APOE4” (Fig. 2j; page unavailable), reports a weak but significant negative correlation between tau pathology and hippocampal volume in PS19-fE4 mice. The Results section on tau pathology identifies AT8 staining as the measure of p-tau pathology in mice assessed at 10 months. (LLM, conf=0.91)

  cites [55] Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023). source

In the paper

“suggesting the contribution of astrocytosis to hippocampal degeneration, as reported previously7”

What the sources say

• Supported

  The paper reports elevated GFAP and activation of reactive-astrocyte genes in 9-month-old TE4 mice; the same passage says the GFAP–brain-volume correlation strongly suggests a detrimental role for reactive astrocytes in neurodegeneration. Extended Data Figure 2 documents hippocampal CA1 neuronal loss in these mice. The citing sentence’s ‘suggesting’ appropriately preserves the paper’s uncertainty about contribution. (LLM, conf=0.88)

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). source

In the paper

“PS19-E4 mice exhibited significantly reduced hippocampal volume compared to WT and PS19-E3 mice (Fig. 4a,b and Extended Data Fig. 2a), as reported previously7,55.”

What the sources say

• Partly supported

  The Abstract reports significantly greater atrophy in 9-month-old P301S/E4 mice than in P301S/E3 mice and identifies the hippocampus as a primary site. However, Methods > Animals explicitly says the authors did not perform statistical comparisons between WT and the other mice, so the claimed significant difference from WT is not supported. (LLM, conf=0.90)

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section, “Neurodegeneration is reduced after removal of neuronal APOE4” (page unavailable), reports greater neurodegeneration in PS19-fE4 than PS19-fE3 mice based on hippocampal and ventricular volumes. It does not report the claimed hippocampal-volume comparison with WT mice, so that part is unsupported by this source. (LLM, conf=0.85)

  cites [55] Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023). sourceExperimental — accuracy not yet measured

In the paper

“Some DE genes recently identified as markers of DAOs in AD mouse models61 were also upregulated in cluster 9 versus cluster 2, such as those mediating the inflammatory process (H2-D1, Il33 and C4b)”

What the sources say

• Supported

  The Results section, “Identification of a disease-associated oligodendrocyte state,” identifies H2-D1, Il33 and C4b as immune-related genes significantly upregulated in disease-associated oligodendrocytes in an AD mouse model. The cluster 9 versus cluster 2 comparison is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.93)

  cites [61] Kenigsbuch, M. et al. A shared disease-associated oligodendrocyte signature among multiple CNS pathologies. Nat. Neurosci. 25, 876–886 (2022). source

In the paper

“that a single copy of the R136S mutation is not sufficient to overcome the detrimental effects of APOE4 on neuronal Tau pathology”

What the sources say

• Partly supported

  The paper’s main text (indexed under Abstract; page unavailable) reports that four PSEN1 mutation carriers with one APOE3 Christchurch (R136S) copy developed mild cognitive impairment at a mean age of 45, and postulates that two copies are required to postpone clinical onset. It does not establish that one copy fails to counteract APOE4 specifically, or assess neuronal tau pathology in those single-copy carriers. (LLM, conf=0.84)

  cites [36] Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Previous work showed that HSPGs are largely responsible for neuronal Tau uptake46–48,57.”

What the sources say

• Partly supported

  The Results (‘Functional genomics to find modulators of tau uptake,’ page unavailable) report that knockdown of HSPG-biosynthesis genes reduced tau uptake in iPS-derived neurons. The Results (‘Cellular internalization of tau is effected by the presence of 6-O-sulfation,’ page unavailable) also report inhibited uptake in those neurons when heparin or heparan sulfate was added. These findings support an important role for HSPGs, but the text does not establish that they account for most neuronal tau uptake. (LLM, conf=0.78)

  cites [46] Rauch, J. N. et al. Tau internalization is regulated by 6-O sulfation on heparan sulfate proteoglycans (HSPGs). Sci. Rep. 8, 6382 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The GAG length/sulfation section reports that HSPGs mediate tau aggregate uptake, and Figure 8 shows reduced uptake after HSPG-pathway gene knockouts in HEK293T cells. The paper says the requirements still need evaluation in post-mitotic central nervous system neurons, so it does not establish the claim specifically for neuronal uptake. Page numbers were not supplied. (LLM, conf=0.88)

  cites [47] Stopschinski, B. E. et al. Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau vs. α-synuclein and β-amyloid aggregates. J. Biol. Chem. 293, 10826–10840 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  In “Understanding Cell Uptake” (page not available), the paper says HSPG binding initiates uptake of aggregated Tau seeds into neurons. It specifies that Tau monomers do not trigger uptake through this mechanism, and it does not establish that HSPGs account for most neuronal Tau uptake overall. The claim omits that limitation and overstates the pathway's share of uptake. (LLM, conf=0.86)

  cites [48] Holmes, B. B. & Diamond, M. I. Prion-like properties of Tau protein: the importance of extracellular Tau as a therapeutic target. J. Biol. Chem. 289, 19855–19861 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion says HSPGs mediate binding and internalization of tau aggregates into neurons, and the primary-neuron experiment reports a 43% reduction in full-length tau fibril uptake after Ext1 knockdown. The source supports a major role for HSPGs in neuronal uptake of aggregated tau, but does not establish that they are largely responsible for uptake of Tau in general. (LLM, conf=0.87)

  cites [57] Holmes, B. B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138–E3147 (2013). sourceExperimental — accuracy not yet measured

In the paper

“The DAAs and DAMs have transcriptomic profiles similar to those reported previously in brains of patients with AD and mouse models62,63.”

What the sources say

• Partly supported

  The paper reports overlap between DAA genes and a previously described DAM signature, and Extended Data Figure 9 compares mouse DAA profiles with astrocytes from human AD and non-AD brains. The Methods state that the DAM signature came from prior literature; this paper does not establish that both DAA and DAM profiles resemble profiles previously reported in human AD brains. (LLM, conf=0.82)

  cites [62] Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable) identify a distinct DAM gene-expression profile in an AD mouse model. The Introduction (page unavailable) reports DAM-marker staining in human AD brains, but not a comparison with previously reported human transcriptomic profiles. The paper does not address DAAs, so it supports only the DAM portion of the claim. (LLM, conf=0.84)

  cites [63] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). sourceExperimental — accuracy not yet measured

In the paper

“by substituting a positively charged arginine residue for the uncharged serine, the affinity of the receptor-binding domain of APOE-R136S for negatively charged HSPGs is greatly diminished36,45,58”

What the sources say

• Partly supported

  The Abstract reports that ApoE3 Christchurch (R136S) had the lowest heparin-binding ability among the ApoE isoforms tested, supporting reduced binding. But the Methods describe the substitution as 136Arg→Ser—the reverse of the direction stated in the claim—and the experiment measured heparin binding, not affinity for HSPGs directly. (LLM, conf=0.88)

  cites [36] Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results identify the Arg136→Ser substitution, and the Discussion says it could alter receptor binding. But the paper does not show that APOE-R136S has greatly diminished affinity for HSPGs. Its preliminary heparin experiment compares the variant with another APOE2 variant, not with unmutated APOE, and finds equal affinity under denaturing conditions (Discussion; page unavailable). (LLM, conf=0.86)

  cites [45] Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R. & Carrell, R. W. Apolipoprotein E2-Christchurch (136 Arg–Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J. Clin. Invest. 80, 483–490 (1987). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [58] Lalazar, A. et al. Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions. J. Biol. Chem. 263, 3542–3545 (1988). source

In the paper

“The original patient showed AD protection with the homozygous APOE3-R136S mutation36.”

What the sources say

• Supported

  The Abstract reports that the patient developed mild cognitive impairment nearly three decades later than expected and had two copies of the APOE3 Christchurch (R136S) mutation. It identifies APOE3ch homozygosity as her most likely genetic modifier, while acknowledging that other factors may have contributed to her resistance. (LLM, conf=0.92)

  cites [36] Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). source

In the paper

“APOE4 exacerbates these phenotypes in a PS19 tauopathy model7,11,55.”

What the sources say

• Supported

  The paper’s main text (indexed under Abstract; page unavailable) describes a P301S tauopathy mouse model and reports that ApoE4 increased brain atrophy and neuronal loss relative to ApoE2 and ApoE3. It also reports higher tau levels and greater neuroinflammation in P301S/E4 mice, supporting the attributed exacerbation of tauopathy phenotypes. (LLM, conf=0.92)

  cites [7] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). source
• Supported

  The Animals section identifies the P301S tauopathy mice crossed with human APOE4 knock-in mice as TE4. In the Results sections on microglial ablation and tau pathogenesis (page numbers unavailable), control TE4 mice show greater brain atrophy and more advanced tau pathology than mice lacking Apoe, supporting the claim in that comparison. (LLM, conf=0.91)

  cites [11] Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546–2561 (2019). source
• Supported

  In the Results (page unavailable), PS19 mice expressing APOE4 had more hippocampal tau pathology and microgliosis than those expressing APOE3. The Results also report greater myelin loss in PS19-APOE4 mice, supporting the claim that APOE4 exacerbates these disease phenotypes in this tauopathy model. (LLM, conf=0.92)

  cites [55] Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023). source

In the paper

“The top predicted off-target cut sites in coding regions by CHOPCHOP78 and COSMID79 were verified to be intact by Sanger sequencing.”

What the sources say

• ?Could not verify

  The Abstract describes ampliCan as a tool for analyzing high-throughput amplicon sequencing, and the Methods discuss filtering reads that may come from off-target amplification. Our copy does not report Sanger sequencing of predicted coding-region off-target sites or verify that those sites were intact (searched: Sanger, COSMID, and off-target-site verification). (LLM, conf=0.76)

  cites [78] Labun, K. et al. Accurate analysis of genuine CRISPR editing events with ampliCan. Genome Res 29, 843–847 (2019). sourceExperimental — accuracy not yet measured
• Supported

  The citation is attached to COSMID, identifying the prediction tool used by the citing authors. The Results section, “COSMID has better ability in identifying off-target sites with indels,” describes COSMID as a tool for searching for predicted off-target sites. The citing authors’ Sanger-sequencing result is not attributed to this source. (LLM, conf=0.93)

  cites [79] Cradick, T. J., Qiu, P., Lee, C. M., Fine, E. J. & Bao, G. COSMID: a web-based tool for identifying and validating CRISPR/Cas off-target sites. Mol. Ther. Nucleic Acids 3, e214 (2014). source

In the paper

“The most advanced type 4 p-Tau staining was enriched in PS19-E4 mice, with roughly 90% of sections analyzed showing type 3 or type 4 p-Tau staining (Fig. 1h).”

In the paper

“The E4-R/S neurons did not show such an effect on APOE protein levels (Fig. 2a,b and Supplementary Fig. 3a).”

In the paper

“whereas no such effect was seen in E4-R/S neurons (Fig. 2e,f).”

In the paper

“Remarkably, PS19-E4-S/S mice exhibited markedly reduced p-Tau accumulation, roughly to the levels in PS19-E3 mice (Fig. 1b,c).”

In the paper

“Additionally, they all expressed stem cell markers Nanog, OCT3/4, SOX2 and TRA-1-60 (Extended Data Fig. 3b).”

In the paper

“Notably, the number of AT8+ soma in the CA1 cell layer strongly correlated with the percent AT8 coverage area in the hippocampus (Supplementary Fig. 1b).”

In the paper

“The E4-S/S neurons also had a lower ratio of APOE fragment/full-length APOE than E4 neurons at both the individual hiPSC line level and the combined hiPSC line level (Supplementary Fig. 2e,f)”

In the paper

“The E4-S/S neurons showed an approximately 40% reduction in p-Tau levels compared to E4 neurons at both the combined hiPSC line level (Fig. 2c,d) and the individual hiPSC line level (Supplementary Fig. 3b,c).”

In the paper

“APOE and glial fibrillary acidic protein (GFAP) double immunostaining confirmed high APOE expression in astrocytes of E4-S/S-KI mice (Extended Data Fig. 1f), identical to that seen in astrocytes of the parental E4-KI mice (Extended Data Fig. 1f).”

In the paper

“We also observed some beading patterns in PHF1+ neurites, suggesting p-Tau aggregates and/or degenerating neurites, which were the least prevalent in E4-S/S neurons (Fig. 2e, arrowheads, and Fig. 2g).”

In the paper

“Notably, E4-R/S neurons did not show the same reduction of p-Tau levels (Fig. 2a,c,d and Supplementary Fig. 3b,c).”

In the paper

“Likewise, immunocytochemical staining with the PHF1 antibody also revealed an approximately 35% reduction in p-Tau levels in E4-S/S neurons versus E4 neurons (Fig. 2e,f)”

In the paper

“Both PS19-E4 and PS19-E4-R/S mice had significantly more AT8+ soma in CA1 than PS19-E3 and PS19-E4-S/S mice (Supplementary Fig. 1a).”

In the paper

“Hippocampal lysates of PS19-E4 mice had significantly higher p-Tau levels than those of PS19-E3 mice at 10 months of age, as determined by western blotting with AT8 and PHF1 antibodies (Fig. 1d–f).”

In the paper

“The E4-S/S neurons had a five-fold increase in APOE protein levels compared to E4 neurons (Fig. 2a,b and Supplementary Fig. 3a).”

In the paper

“The E4-S/S neuron cultures showed a similar proportion of GABA+ inhibitory neurons to the E3 neuron cultures (Supplementary Fig. 2c,d)”

In the paper

“This reduction was not seen in PS19-E4-R/S mice (Fig. 1b,c)”

In the paper

“both GFAP and S100β coverage areas (Extended Data Fig. 5c,g) and cell numbers (Fig. 5e,i) inversely correlated with hippocampal volume in 10-month-old PS19-E4 mice”

In the paper

“The PS19-E4 mice exhibited significantly higher microglia immunoreactivity (both coverage area and cell number) via measurements of both markers than the PS19-E3, PS19-E4-S/S and PS19-E4-R/S mice”

In the paper

“it positively correlated with astrocytosis (Supplementary Fig. 6e,f,i,j)”

In the paper

“the relationship between microgliosis and hippocampal degeneration in PS19-E3 and PS19-E4 mice was somewhat preserved”

In the paper

“Similar results were obtained for quantifications of activated astrocyte (S100β+) coverage area and cell numbers (Fig. 5c,d and Extended Data Fig. 5b).”

In the paper

“both Iba1 and CD68 coverage areas (Extended Data Fig. 5m,q) and cell numbers (Fig. 5q,u) inversely correlated with hippocampal volume in 10-month-old PS19-E4 and PS19-E4-R/S mice”

In the paper

“Tau pathology positively correlated with microgliosis (Supplementary Fig. 6o,p)”

In the paper

“Heparin treatment significantly reduced MFI in E4, E3 and E4-R/S neurons (Fig. 3b)”

In the paper

“The EKO neurons showed a marked decrease in Tau-488 uptake versus E4 neurons, to roughly the level of E4-S/S neurons (Fig. 3b).”

In the paper

“The E3 neurons also showed a trend of reduced Tau-488 uptake (~20%) compared to E4 neurons, although not reaching significance.”

In the paper

“Analysis of correlation between the APOE4-R136S copy number (0, 1 or 2) and the average of hippocampal volume or the average of posterior lateral ventricle volume revealed a clear gene dose-dependent effect of the R136S mutation on the protection of APOE4-promoted hippocampal degeneration (Fig. 4d,e).”

In the paper

“Only E4-S/S and EKO neurons had a significantly reduced fraction (~30%) of cells with internalized Tau-488, as compared to E4 neurons (Fig. 3c).”

In the paper

“although PS19-E4-S/S mice had a trend toward lower astrocytosis as compared to PS19-E4 mice”

In the paper

“PS19-E3 and PS19-E4-S/S mice showed a significant increase (~20%) in DG GC layer thickness over PS19-E4 mice (Fig. 4k).”

In the paper

“The EKO neurons treated with heparin showed a similarly small decrease (Fig. 3b), which represents the APOE-independent but HSPG-dependent Tau-488 uptake.”

In the paper

“The PS19-E4-R/S mice showed significantly higher Iba1+ and CD68+ cell numbers than PS19-E4-S/S mice”

In the paper

“The effect of heparin treatment on the fraction of neurons with internalized Tau-488 was similar in E4 and E4-R/S neurons (Fig. 3c).”

In the paper

“The E4-S/S neurons exhibited an approximately 50% reduction in MFI compared to E4 neurons (Fig. 3b), indicating reduced Tau-488 uptake.”

In the paper

“We also observed a partial rescue of hippocampal atrophy in PS19-E4-R/S mice toward PS19-E3 levels (Fig. 4b).”

In the paper

“In fact, treatment with E4 neuron-conditioned medium (1:1 mixed with fresh medium) for 2 weeks increased p-Tau accumulation in both E3 and E4-S/S neurons to the level of E4 neurons (Fig. 3h,i).”

In the paper

“These relationships disappeared in PS19-E3 and PS19-E4-S/S mice (Fig. 4g,h and Supplementary Fig. 1d,e)”

In the paper

“Notably, a significant correlation was observed between the APOE4-R136S copy number and GFAP+ cell number (Supplementary Fig. 5a).”

In the paper

“PS19 mice at 6 months of age did not show the same differences in astrocytosis across APOE genotype groups”

In the paper

“Similarly, the number of AT8+ soma in CA1 cell layer was negatively correlated to hippocampal volume in PS19-E4 mice (Supplementary Fig. 1c).”

In the paper

“yet positively correlates with microgliosis (Supplementary Fig. 6g,h,k,l)”

In the paper

“It is again notable that E4 neurons treated with heparin reduced the fraction of neurons with internalized Tau-488 to levels seen in E4-S/S neurons and EKO neurons without heparin treatment.”

In the paper

“Again, PS19-E4-R/S mice showed a non-significant increase (12%) in DG GC layer thickness over PS19-E4 mice.”

In the paper

“and PS19-E4-S/S mice (Fig. 5g,k and Extended Data Fig. 5e,i)”

In the paper

“This correlation was mostly eliminated in PS19-E3 mice”

In the paper

“mild microgliosis negatively correlated with hippocampal volume in PS19-E3 and PS19-E4-S/S mice”

In the paper

“No significant difference was observed in hippocampal volume across various APOE genotype groups of 6-month-old mice (Extended Data Fig. 2c,f).”

In the paper

“Strikingly, hippocampal atrophy of PS19-E4-S/S mice was reduced to similar levels of those seen in WT and PS19-E3 mice (Fig. 4a,b).”

In the paper

“These relationships were still present in PS19-E4-R/S mice (Fig. 4i and Supplementary Fig. 1f)”

In the paper

“Notably, E4 neurons treated with heparin exhibited reduction of MFI (~40%) to levels not significantly different from E4-S/S neurons and EKO neurons without heparin treatment.”

In the paper

“Tau pathology had a trending correlation with astrocytosis (Supplementary Fig. 6a,b)”

In the paper

“The PS19-E4-S/S mice did show a trend toward lower microgliosis as compared to PS19-E4 mice”

In the paper

“However, this relationship was preserved in PS19-E4-R/S mice”

In the paper

“In the 6-month-old PS19 mice, we did not observe the same differences in microgliosis across APOE genotype groups.”

In the paper

“Again, the PS19-E4-R/S mice had a partial rescue (Fig. 4c).”

In the paper

“This was confirmed by significant correlation of the APOE4-R136S copy number to Iba1+ cell number”

In the paper

“the Tau pathology positively, albeit weakly, correlated with astrocytosis (Supplementary Fig. 6m,n)”

In the paper

“Notably, heparin treatment did not significantly alter endogenous p-Tau levels in E4-S/S neurons (Fig. 3f).”

In the paper

“microglia subclusters 2 and 11 were likely to contain more cells from PS19-E4-S/S mice than from PS19-E4 mice”

In the paper

“Excitatory neuron clusters 7 (CA2/3) and 28 had significantly higher odds of containing cells from either PS19-E4-S/S or PS19-E4-R/S mice than from PS19-E4 mice”

In the paper

“astrocyte subcluster 3 was enriched in PS19-E3 and PS19-E4-S/S mice, but not in PS19-E4-R/S mice, compared to PS19-E4 mice”

In the paper

“No significant difference was observed in APOE expression in each cell cluster across various APOE genotypes”

In the paper

“PCA analysis revealed that the disease-protective microglia subcluster 2 had a similar contribution to the measured pathologies as the four disease-protective neuronal clusters (1, 6, 7 and 28)”

In the paper

“the R136S mutation eliminated neutral lipid accumulation in microglia in PS19-E4-S/S mice”

In the paper

“Using Nkain2 as a marker for DAA subcluster 5 and Id3 as a marker for DAA subcluster 7, immunofluorescent staining confirmed a significant decrease in both DAA clusters in the hippocampus of PS19-E4-S/S mice versus PS19-E4 mice”

In the paper

“Such PCA analysis revealed that the disease-protective astrocyte subcluster 3 had a similar contribution to the measured pathologies as the four disease-protective neuronal clusters (1, 6, 7 and 28)”

In the paper

“the top enriched DE pathways in these clusters were indicative of neuronal health and function, including axon guidance, synaptic integrity and long-term potentiation”

In the paper

“the proportion of cells in excitatory neuron clusters 1, 6, 7 and 28 exhibited significant positive associations with hippocampal volume and negative associations with the coverage areas of p-Tau and gliosis”

In the paper

“microglia subcluster 8 was likely to contain fewer cells from PS19-E4-S/S mice than from PS19-E4 mice”

In the paper

“GFAP/BODIPY double staining revealed neutral lipid accumulation in astrocytes in PS19-E4 mice”

In the paper

“excitatory neuron cluster 1 (GC) and cluster 6 (CA2/3) had significantly higher odds of containing cells from PS19-E4-S/S mice than from PS19-E4 mice”

In the paper

“Using Gpnmb as a marker for DAM cluster 8, immunofluorescent staining confirmed a significant decrease in this DAM cluster in the hippocampus of PS19-E4-S/S mice versus PS19-E4 mice”

In the paper

“PS19-E4-R/S mice also had a significant decrease in microglia subcluster 8, although to a lesser extent than PS19-E4-S/S mice”

In the paper

“many of these highly upregulated DAO genes unique to cluster 9 were markedly downregulated in PS19-E4-S/S mice versus PS19-E4 mice”

In the paper

“Iba1/BODIPY double staining confirmed neutral lipid accumulation in microglia in PS19-E4 mice but not PS19-E3 mice”

In the paper

“DAA subcluster 7 had enrichment of lipid and atherosclerosis pathway genes”

In the paper

“subcluster 7 was almost completely eliminated in PS19-E4-S/S mice”

In the paper

“astrocyte subclusters 5 and 7 had lower odds of containing cells from PS19-E4-S/S mice than from PS19-E4 mice”

In the paper

“Notably, some DE pathways did differ based on the R136S gene dose.”

In the paper

“Using Kirrel3 as a marker, immunofluorescent staining confirmed a significant decrease in the DAO cluster 9 in the hippocampus of PS19-E4-S/S mice versus PS19-E4 mice”

In the paper

“the APOE4-R136S mutation reduced lysosome size to levels similar to that of the PS19-E3 mice”

In the paper

“the proportion of cells in microglia subclusters 2 and 11 exhibited positive associations with hippocampal volume and negative associations with the coverage areas of p-Tau and gliosis”

In the paper

“astrocytes in PS19-E4 mice had enlarged Lamp1+ lysosomes as compared to those in PS19-E3 mice”

In the paper

“We also observed enrichment of lipid and atherosclerosis pathway genes in DAM subcluster 8”

In the paper

“the DAO cluster 9 had many significantly upregulated genes uniquely identified in the current study, including Kirrel3, Neat1, Apod, Dgki, Fmn1, Pex5l, Sik3 and Grik2”

In the paper

“Likewise, DAM subcluster 8 had a similar contribution to the measured pathologies as the DAOs (cluster 9)”

In the paper

“the R136S mutation eliminated neutral lipid accumulation in astrocytes in PS19-E4-S/S mice”