Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector.
- Authors
- Wang, Chengzhong; Najm, Ramsey; Xu, Qin; Jeong, Dah-Eun; Walker, David; Balestra, Maureen E; Yoon, Seo Yeon; Yuan, Heidi; Li, Gang; Miller, Zachary A; Miller, Bruce L; Malloy, Mary J; Huang, Yadong
- Year
- 2018
- Journal
- Nature medicine
- PMID
- 29632371
- DOI
- 10.1038/s41591-018-0004-z
- PMCID
- PMC5948154
Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-Ξ² (AΞ²) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased AΞ² production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.
Human apoE4/4 neurons generate more apoE fragments, have higher p-tau levels, and produce more AΞ² than human apoE3/3 neurons(a) Western blot analysis of full-length apoE in lysates (intracellular) or medium (secreted) of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. (b) Quantification of full-length apoE in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 23 biologically independent samples from E3/3 (n=9 from apoE3/3-A; n=8 from apoE3/3-B; n=6 from apoE3/3-C), n = 20 biologically independent samples from E4/4 (n=6 from apoE4/4-A; n=6 from apoE4/4-B; n=8 from apoE4/4-C). (c) Quantification of full-length apoE in culture medium of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 15 biologically independent samples from E3/3 (n=6 from apoE3/3-A; n=6 from apoE3/3-B; n=3 from apoE3/3-C), n = 9 biologically independent samples from E4/4 (n=3 from apoE4/4-A; n=3 from apoE4/4-B; n=3 from apoE4/4-C). (d) Western blot analysis of full-length apoE and apoE fragments in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. (e) Quantification of apoE fragments in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 13 biologically independent samples from E3/3 (n=3 from apoE3/3-A; n=5 from apoE3/3-B; n=5 from apoE3/3-C), n = 14 biologically independent samples from E4/4 (n=3 from apoE4/4-A; n=5 from apoE4/4-B; n=6 from apoE4/4-C). (f) Western blot analysis of p-tau with AT8, AT180, PHF1, and AT270 monoclonal antibodies in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. (g) Quantification of p-tau (AT8) in neuronal lysates. Values are normalized to E3/3. n = 31 biologically independent samples from E3/3 and n = 25 biologically independent samples from E4/4. (h) Quantification of p-tau (AT180) in neuronal lysates. Values are normalized to E3/3. n = 22 biologically independent samples from E3/3 (n=7 from apoE3/3-A; n=7 from apoE3/3-B; n=8 from apoE3/3-C), n = 18 biologically independent samples from E4/4 (n=6 from apoE4/4-A; n=4 from apoE4/4-B; n=8 from apoE4/4-C). (i) Quantification of p-tau (PHF1) in neuronal lysates. Values are normalized to E3/3. n = 17 biologically independent samples from E3/3 (n=4 from apoE3/3-A; n=6 from apoE3/3-B; n=7 from apoE3/3-C), n = 25 biologically independent samples from E4/4 (n=8 from apoE4/4-A; n=8 from apoE4/4-B; n=9 from apoE4/4-C). (j) Quantification of p-tau (AT270) in neuronal lysates. Values are normalized to E3/3. n = 23 biologically independent samples from E3/3 (n=10 from apoE3/3-A; n=10 from apoE3/3-B; n=3 from apoE3/3-C), n = 17 biologically independent samples from E4/4 (n=10 from apoE4/4-A; n=4 from apoE4/4-B; n=3 from apoE4/4-C). (k) Immunostaining for MAP2 and p-tau (AT8 and PHF1) in neuronal cultures derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Scale bar, 50 Β΅m. (l, m) Quantification of the percentage of MAP2-positive neurons that are also positive for p-tau (AT8 and PHF1) in neuronal cultures derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. n = 12 (E3/3: n=12 fields with total of 594 MAP2+ neurons counted for AT8; n=12 fields with total of 945 MAP2+ neurons counted for PHF1), n = 12 (E4/4: n=12 fields with total of 526 MAP2+ neurons counted for AT8; n=12 fields with total of 1030 MAP2+ neurons counted for PHF1). (n) AΞ²40 levels in culture medium of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. n = 23 biologically independent samples from E3/3 (n=4 from apoE3/3-A; n=7 from apoE3/3-B; n=12 from apoE3/3-C), n = 21 biologically independent samples from E4/4 (n=5 from apoE4/4-A; n=4 from apoE4/4-B; n=12 from apoE4/4-C). (o) AΞ²42 levels in culture medium of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. n = 23 biologically independent samples from E3/3 (n=4 from apoE3/3-A; n=7 from apoE3/3-B; n=12 from apoE3/3-C), n = 21 biologically independent samples from E4/4 (n=5 from apoE4/4-A; n=4 from apoE4/4-B; n=12 from apoE4/4-C). (p) Western blot analysis of sAPP in culture medium of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. (q) Quantification of sAPP in culture medium of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 15 biologically independent samples from E3/3 (n=6 from apoE3/3-A; n=6 from apoE3/3-B; n=3 from apoE3/3-C), n = 6 biologically independent samples from E4/4 (n=2 from apoE4/4-A; n=2 from apoE4/4-B; n=2 from apoE4/4-C). (r) Western blot analysis of APP with 22C11 monoclonal antibody in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. (s) Quantification of APP, as determined by 22C11 monoclonal antibody, in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 11 biologically independent samples from E3/3 (n=4 from apoE3/3-A; n=4 from apoE3/3-B; n=3 from apoE3/3-C), n = 19 biologically independent samples from E4/4 (n=3 from apoE4/4-A; n=8 from apoE4/4-B; n=8 from apoE4/4-C). (t) Quantification of APP mRNA levels by qRT-PCR in neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 12 biologically independent samples from E3/3 (n=4 from apoE3/3-A; n=4 from apoE3/3-B; n=4 from apoE3/3-C), n = 12 biologically independent samples from E4/4 (n=4 from apoE4/4-A; n=4 from apoE4/4-B; n=4 from apoE4/4-C). (u) Tuj1/actin ratios in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 11 biologically independent samples from E3/3 (n=4 from apoE3/3-A; n=4 from apoE3/3-B; n=3 from apoE3/3-C), n = 19 biologically independent samples from E4/4 (n=3 from apoE4/4-A; n=8 from apoE4/4-B; n=8 from apoE4/4-C). All values are expressed as mean Β± SEM. Differences between groups were determined with the unpaired two-sided t test.
Increased p-tau levels in apoE4/4 neurons are independent of higher AΞ² production(a) AΞ²40 levels in culture medium of apoE4/4 neurons treated with vehicle (control), a Ξ²-secretase inhibitor (OM99-2, 750 nM), or a Ξ³-secretase inhibitor (compound E, Copd-E, 200 nM) for 1 week. n = 4 (control), n = 3 (OM99-2), and n = 3 (Copd-E) biologically independent samples. (b) AΞ²42 levels in culture medium of apoE4/4 neurons treated with vehicle (control), a Ξ²-secretase inhibitor (OM99-2), or a Ξ³-secretase inhibitor (Copd-E) for 1 week. n = 4 (control), n = 3 (OM99-2), and n = 3 (Copd-E) biologically independent samples. (c) Western blot analysis of p-tau with AT8 and AT180 monoclonal antibodies in lysates of apoE4/4 neurons treated with vehicle (control), a Ξ²-secretase inhibitor (OM99-2), or a Ξ³-secretase inhibitor (Copd-E) for 1 week. (d) Quantification of p-tau (AT8) in lysates of apoE4/4 neurons treated with vehicle (control), a Ξ²-secretase inhibitor (OM99-2), or a Ξ³-secretase inhibitor (Copd-E) for 1 week. Values are normalized to control. n = 8 (control), n = 8 (OM99-2), and n = 8 (Copd-E) biologically independent samples. (e) Quantification of p-tau (AT180) in lysates of apoE4/4 neurons treated with vehicle (control), Ξ²-secretase inhibitor (OM99-2), or Ξ³-secretase inhibitor (Copd-E) for 1 week. Values are normalized to control. n = 8 (control), n = 8 (OM99-2), and n = 8 (Copd-E) biologically independent samples. All values are expressed as mean Β± SEM. Differences among groups were determined with one-way ANOVA followed with Tukeyβs multiple comparison test. ***p < 0.001 versus E4/4-Control.
ApoE4 causes GABAergic neuron degeneration/loss in hiPSC-derived neuronal culture(a, b) Double immunostaining for GABA and MAP2 in neuronal cultures derived from apoE3/3-hiPSCs (a) and apoE4/4-hiPSCs (b). Scale bar, 100 Β΅m. (c) Quantification of GABA-positive cells per field in neuronal cultures derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 36 fields from E3/3 (n=16 from apoE3/3-A; n=12 from apoE3/3-B; n=8 from apoE3/3-C, with total of 9325 GABA+ neurons counted), n = 32 fields from E4/4 (n=12 from apoE4/4-A; n=12 from apoE4/4-B; n=8 from apoE4/4-C, with total of 3433 GABA+ neurons counted). (d) Western blot analysis of GAD65/67 in lysates of neurons derived from individual lines of apoE3/3-hiPSCs and apoE4/4-hiPSCs. (e) Quantification of the ratios of GAD65/67 to Tuj1 in lysates of neurons derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. Values are normalized to E3/3. n = 54 biologically independent samples from E3/3 (n=20 from apoE3/3-A; n=25 from apoE3/3-B; n=9 from apoE3/3-C), n =35 biologically independent samples from E4/4 (n=14 from apoE4/4-A; n=12 from apoE4/4-B; n=9 from apoE4/4-C). (f, g) Double immunostaining for GABA and AT8 (p-tau) in neuronal cultures derived from apoE3/3-hiPSCs (f) and apoE4/4-hiPSCs (g). Scale bar, 25 Β΅m. (h) Quantification of the percentage of GABA-positive cells that are also positive for AT8 (p-tau) in neuronal cultures derived from apoE3/3-hiPSCs and apoE4/4-hiPSCs. n = 12 fields from E3/3 (n=4 from apoE3/3-A; n=4 from apoE3/3-B; n=4 from apoE3/3-C, with total of 352 GABA+ neurons counted), n = 12 fields from E4/4 (n=4 from apoE4/4-A; n=4 from apoE4/4-B; n=4 from apoE4/4-C, with total of 144 GABA+ neurons counted). (i) Western blot analysis of p-tau (AT8 and PHF1) in lysates of pure GABAergic neurons generated from apoE3/3-hiPSCs and apoE4/4-hiPSCs. (j) Quantification of p-tau (AT8) in GABAergic neuron lysates. Values are normalized to E3/3. n = 10 biologically independent samples from E3/3 (n=5 from E3/3-A; n=5 from E3/3-B), n = 10 biologically independent samples from E4/4 (n=5 from E4/4-A; n=5 from E4/4-B). (k) Quantification of p-tau (PHF1) in GABAergic neuron lysates. Values are normalized to E3/3. n = 10 biologically independent samples from E3/3 (n=5 from E3/3-A; n=5 from E3/3-B), n = 10 biologically independent samples from E4/4 (n=5 from E4/4-A; n=5 from E4/4-B). (l, m) Double immunostaining for p-tau (PHF1) and total tau in GABAergic neurons generated from apoE4/4-hiPSCs (l) and apoE3/3-hiPSCs (m). The experiments were repeated independently for over three times with similar results. Scale bar, 25Β΅m. All values are expressed as mean Β± SEM. Differences between groups were determined with the unpaired two-sided t test in c, e, and h. Differences among groups were determined by two-way ANOVA followed with Sidakβs multiple comparisons test in j and k. **p < 0.01; ***p < 0.001.
AD-related pathologies in human apoE4/4 neurons are specifically induced by apoE4(a) Quantification of the full-length apoE in lysates of neurons derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). Values are normalized to E4/4. n = 3 (E4/4) and n = 6 (iE3/3) biologically independent samples. (b) Quantification of apoE fragments in lysates of neurons derived from apoE4/4-hiPSCs and the isogenic apoE3/3-hiPSCs (iE3/3). Values are normalized to E4/4. n = 3 (E4/4) and n = 6 (iE3/3) biologically independent samples. (c) AΞ²40 levels in culture medium of neurons derived from apoE4/4-hiPSCs and the isogenic apoE3/3-hiPSCs (iE3/3). n = 8 (E4/4) and n = 6 (iE3/3) biologically independent samples. (d) AΞ²42 levels in culture medium of neurons derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). n = 8 (E4/4) and n = 6 (iE3/3) biologically independent samples. (e) Western blot analysis for p-tau (PHF1 and AT8) and GAD67 in lysates of neurons derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). (f, g) Quantification of p-tau levels determined with monoclonal antibodies PHF1 (f) and AT8 (g) in lysates of neurons derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). Values are normalized to E4/4. n = 8 (E4/4) and n = 6 (iE3/3) biologically independent samples. (h) Quantification of GAD67 levels in lysates of neurons derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). Values are normalized to E4/4. n = 14 (E4/4) and n = 20 (iE3/3) biologically independent samples. (i, j) Double immunostaining for AT8 and MAP2 in neurons derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). Scale bar, 50 Β΅m. (k) Quantification of the percentage of MAP2-positive cells that are also positive for AT8 (p-tau) in neuronal cultures derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). n = 8 fields from E4/4 with total of 1533 MAP2+ neurons counted, n = 8 fields from iE3/3 with total of 1691 MAP2+ neurons counted. (l, m) Double immunostaining for GABA and MAP2 in neurons derived from apoE4/4-hiPSCs and isogenic apoE3/3-hiPSCs (iE3/3). Scale bar, 50 Β΅m. (n) Quantification of GABA-positive cells per field in neuronal cultures derived from apoE4/4-hiPSCs and the isogenic apoE3/3-hiPSCs (iE3/3). Values are normalized to E4/4 group. n = 8 fields from E4/4 with total of 149 GABA+ neurons counted), n = 8 fields from iE3/3 with total of 359 GABA+ neurons counted). All values are expressed as mean Β± SEM. Differences between groups were determined with the unpaired two-sided t test.
ApoE4 confers a gain of toxic effects in hiPSC-derived neurons(a, b) Quantification of p-tau levels determined with monoclonal antibodies AT8 (a) and PHF1 (b) in lysates of neurons derived from isogenic apoE3/3-hiPSCs (iE3/3) and apoEβ/β hiPSCs (Eβ/β). Values are normalized to iE3/3. n = 7 (iE3/3) and n = 7 (Eβ/β) biologically independent samples. (c) AΞ²40 levels in culture medium of neurons derived from isogenic apoE3/3-hiPSCs (iE3/3) and apoEβ/β hiPSCs (Eβ/β). Values are normalized to iE3/3. n = 7 (iE3/3) and n = 7 (Eβ/β) biologically independent samples. (d) AΞ²42 levels in culture medium of neurons derived from isogenic apoE3/3-hiPSCs (iE3/3) and apoEβ/β hiPSCs (Eβ/β). Values are normalized to iE3/3. n = 7 (iE3/3) and n = 7 (Eβ/β) biologically independent samples. (e, f) Immunostaining for MAP2 and GABA in neuronal cultures derived from isogenic apoE3/3-hiPSCs (iE3/3) (e) and apoEβ/β hiPSCs (Eβ/β) (f). Scale bar is 50 Β΅m. (g) Quantification of GABA-positive cells per field in neuronal cultures derived from isogenic apoE3/3-hiPSCs (iE3/3) and apoEβ/β hiPSCs (Eβ/β). Values are normalized to iE3/3. n = 6 fields from iE3/3 with total of 3520 GABA+ neurons counted, n = 6 fields from Eβ/β with total of 3897 GABA+ neurons counted. (h) Western blot analyses of apoE expression and p-tau (PHF1) levels in lysates of apoE-null neurons transfected with a control lentiviral vector (+Con), a lentiviral apoE3 construct (+E3), or a lentiviral apoE4 construct (+E4). (i) Quantification of the full-length apoE in lysates of apoE-null neurons transfected with a lentiviral apoE3 construct (+E3), or a lentiviral apoE4 construct (+E4). Values are normalized to +E3. n = 3 (+E3) and n = 3 (+E4) biologically independent samples. (j) Quantification of p-tau (PHF1) levels in lysates of apoE-null neurons transfected with a control lentiviral vector (+Con), a lentiviral apoE3 construct (+E3), or a lentiviral apoE4 construct (+E4). Values are normalized to +Con. n = 3 (+Con), n = 3 (+E3), and n = 3 (+E4) biologically independent samples. (kβm) Anti-GABA immunostaining of apoE-null neurons transfected with a control lentiviral vector (+Con), a lentiviral apoE3 construct (+E3), or a lentiviral apoE4 construct (+E4). Scale bar, 50 Β΅m. (n) Quantification of GABA-positive cells per field in apoE-null neuronal cultures transfected with a control lentiviral vector (+Con), a lentiviral apoE3 construct (+E3), or a lentiviral apoE4 construct (+E4). Values are normalized to +Con. n = 8 fields from +Con with total of 1104 GABA+ neurons counted, n = 8 fields from +E3 with total 1234 of GABA+ neurons counted, n = 8 fields from +E4 with total of 637 GABA+ neurons counted. (o) AΞ²40 levels in culture medium of apoE-null neurons transfected with a control lentiviral vector (+Con), a lentiviral apoE3 construct (+E3), or a lentiviral apoE4 construct (+E4). Values are normalized to +Con. n = 3 (+Con), n = 3 (+E3), and n = 3 (+E4) biologically independent samples. (p) AΞ²42 levels in culture medium of apoE-null neurons transfected with a control lentiviral vector (+Con), a lentiviral apoE3 construct (+E3), or a lentiviral apoE4 construct (+E4). Values are normalized to +Con. n = 3 (+Con), n = 3 (+E3), and n = 3 (+E4) biologically independent samples. All values are expressed as mean Β± SEM. Differences between groups were determined with the unpaired two-sided t test in aβd, g, and i. Differences among groups were determined with one-way ANOVA followed with Tukeyβs multiple comparison test in j and nβp. *p < 0.05; **p < 0.01.
The gain of toxic effects of apoE4 in hiPSC-derived neurons can be ameliorated by a small-molecule structure corrector(a) Western blot analysis of apoE fragment levels in lysates of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with dimethyl sulfoxide (DMSO) or the small-molecule structure corrector PH002. (b) Quantification of apoE fragment levels in lysates of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with DMSO or PH002. Values are normalized to E4/4. n = 5 (E3/3), n = 5 (E4/4), n = 6 (E4/4+DMSO), and n = 6 (E4/4+PH002) biologically independent samples. (c) Quantification of GABA-positive cells per field in cultures of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with DMSO or PH002. Values are normalized to E3/3. n = 6 fields from E3/3 with total of 3071 GABA+ neurons counted) n = 6 fields from E4/4 with total of 1223 GABA+ neurons counted), n = 3 fields from E3/3+DMSO with total of 1358 GABA+ neurons counted), n = 3fields from E4/4+DMSO with total of 511 GABA+ neurons counted, n = 3 fields from E4/4+PH002 with total of 1077 GABA+ neurons counted. (d) Western blot analyses of p-tau (AT8) and GAD67 in lysates of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with DMSO or PH002. (e) Quantification of p-tau (AT8) levels in lysates of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with DMSO or PH002. Values are normalized to E3/3. n = 6 (E3/3), n = 7 (E4/4), n = 5 (E3/3+DMSO), n = 8 (E4/4+DMSO), and n = 8 (E4/4+PH002) biologically independent samples. (f) Quantification of GAD67 levels in lysates of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with DMSO or PH002. Values are normalized to E3/3. n = 7 (E3/3), n = 7 (E4/4), n = 5 (E3/3+DMSO), n = 8 (E4/4+DMSO), and n = 6 (E4/4+PH002) biologically independent samples. (g) AΞ²40 levels in culture medium of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with DMSO or PH002. n = 4 (E3/3), n = 4 (E4/4), n = 3 (E4/4+DMSO), and n = 3 (E4/4+PH002) biologically independent samples. (h) AΞ²42 levels in culture medium of apoE3/3 neurons, apoE4/4 neurons, and apoE4/4 neurons treated with DMSO or PH002. n = 4 (E3/3), n = 4 (E4/4), n = 3 (E4/4+DMSO), and n = 3 (E4/4+PH002) biologically independent samples. (iβl) Dose effects of PH002 treatment on AΞ²40 (i), AΞ²42 (j), p-tau (PHF1) (k), and GAD67 (l) levels in culture medium or cell lysates of apoE4/4 neurons. DMSO treatment was used as a control. n = 4 biologically independent samples for each treatment group. All values are expressed as mean Β± SEM. Differences among groups were determined with one-way ANOVA followed with Tukeyβs multiple comparison test. *p < 0.05; **p < 0.01; ***p < 0.001 versus E4/4 or E4/4+DMSO in b, c, and eβh. *p < 0.05; **p < 0.01; ***p < 0.001 versus E4/4+DMSO in iβl.
| Name | Type |
|---|---|
| 22C11 antibody local | drug |
| 2-mercaptoethanol | drug |
| accutase | drug |
| ACM local | drug |
| ACTB | gene |
| actin | drug |
| actin antibody local | drug |
| AD patients | cohort |
| AD-related pathologies local | phenotype |
| AD-related phenotypes local | phenotype |
| Alexa Fluor 488 | drug |
| Alexa Fluor 594 | drug |
| Alzheimer's disease | phenotype |
| Amyloid beta | drug |
| Amyloid-beta peptide | drug |
| Amyloid plaque formation local | phenotype |
| amyloid plaques | phenotype |
| animal models | cohort |
| apoE | gene |
| apoEβ/β local | cohort |
| APOEβ/β local | variant |
| apoE3 local | drug |
| apoE3 local | variant |
| ApoE3 local | variant |
| APOE3 local | drug |
| APOE3 local | variant |
| apoE3/3 local | variant |
| APOE3/3 local | variant |
| apoE336β38 local | variant |
| apoE3/3-hiPSC local | cohort |
| APOE3/3 hiPSC-derived neurons local | cohort |
| apoE3/3-hiPSC line local | cohort |
| apoE3/3-hiPSC line (iE3/3) local | cohort |
| APOE3/3 hiPSC lines local | cohort |
| apoE3/3-hiPSCs local | cohort |
| APOE3/3-hiPSCs local | cohort |
| apoE3/3-miPSCs local | cohort |
| APOE3/3 neurons local | cohort |
| APOE3 allele local | variant |
| APOE3-KI local | variant |
| apoE4 local | drug |
| apoE4 | gene |
| APOE4 local | drug |
| apoE4/4 local | variant |
| apoE4/4-hiPSC local | cohort |
| apoE4/4-hiPSC-A line local | cohort |
| apoE4/4-hiPSC line local | cohort |
| APOE4/4 hiPSC lines local | cohort |
| apoE4/4-hiPSCs local | cohort |
| APOE4/4-hiPSCs local | cohort |
| apoE4/4-miPSCs local | cohort |
| APOE4/4 neurons local | cohort |
| APOE4 allele local | variant |
| APOE4-KI local | variant |
| apoE4 knock-in mice local | cohort |
| apoE4 structure corrector local | drug |
| apoE antibody local | drug |
| APOE Arg112 local | variant |
| apoE deficiency local | phenotype |
| apoE-deficient hiPSCs local | cohort |
| apoE-deficient lines local | cohort |
| apoE fragmentation local | phenotype |
| apoE fragment levels local | phenotype |
| apoE fragments local | drug |
| ApoE fragments local | drug |
| APOE-ZFN local | drug |
| APOE Ξ΅3 local | variant |
| APOE-Ξ΅3 local | variant |
| APOE Ξ΅4 | gene |
| APOE-Ξ΅4 | gene |
| APP | gene |
| APP mRNA local | drug |
| Arg-112 local | variant |
| Arg-61 local | variant |
| astrocyte progenitors local | cohort |
| astrocytes local | cohort |
| astrocytes | phenotype |
| Astrocytes local | cohort |
| AT180 local | drug |
| AT180 antibody local | drug |
| AT270 local | drug |
| AT270 local | gene |
| AT270 antibody local | drug |
| AT8 antibody local | drug |
| axonal degeneration | phenotype |
| AΞ² local | phenotype |
| AΞ²40 local | drug |
| AΞ²40 local | phenotype |
| AΞ²40 secretion local | phenotype |
| AΞ²42 local | drug |
| AΞ²42 local | phenotype |
| AΞ²42 secretion local | phenotype |
| AΞ² accumulation | phenotype |
| AΞ² production | phenotype |
| B27 supplement | drug |
| Bace1 | gene |
| BCA protein assay kit | drug |
| Bdnf | gene |
| bFGF | drug |
| bone morphogenetic protein receptor local | gene |
| brain | anatomy |
| brain-derived neurotrophic factor | drug |
| CASP3 | gene |
| Caspase-3 | gene |
| cerebrospinal fluid | drug |
| collagenase IV local | drug |
| compound E | drug |
| cultured human neurons local | anatomy |
| Cys-112 local | variant |
| DAPI | drug |
| DAPT | drug |
| Dementia in AD patients local | phenotype |
| dimethyl sulfoxide | drug |
| DMEM/F12 | drug |
| dopaminergic neurons | anatomy |
| EGF | drug |
| endoplasmic reticulum | anatomy |
| Excitatory neuron local | cohort |
| FGF-8 local | drug |
| FOXG1 | gene |
| full-length apoE levels local | phenotype |
| full-length APP protein local | drug |
| Full-length intracellular apoE local | drug |
| Full-length secreted apoE local | drug |
| GABA | phenotype |
| GABAergic neuron degeneration local | phenotype |
| GABAergic neurons local | cohort |
| GABA-positive neurons local | phenotype |
| GAD1 | gene |
| GAD2 | gene |
| GAD65/67 local | drug |
| GAD65/67 antibody local | drug |
| GAD67 antibody local | drug |
| GAD67 levels local | phenotype |
| GDNF | drug |
| GenElute Mammalian Genomic DNA Miniprep Kit local | drug |
| gene-targeted mice local | cohort |
| genotype effects local | phenotype |
| GFAP | gene |
| GFAP antibody | drug |
| glial cellβderived growth factor local | drug |
| Glu-255 local | variant |
| glutamatergic neurons local | cohort |
| glutamatergic neurons | phenotype |
| Glutamax | drug |
| glutamine | drug |
| Golgi apparatus local | anatomy |
| HEK293 cells | cohort |
| heparin | drug |
| hES cell medium local | drug |
| hES medium local | drug |
| high purity neuronal culture local | phenotype |
| Hippocampal network activity impairment local | phenotype |
| hippocampus | anatomy |
| hiPSC-derived neurons | cohort |
| hiPSC line local | cohort |
| hiPSC lines | cohort |
| hiPSCs | cohort |
| Human ApoE (AD2) ELISA kit local | drug |
| Human AΞ² peptide local | phenotype |
| human neurons local | drug |
| Human Stem Cell Nucleofector Kit I local | drug |
| hyperphosphorylated tau | drug |
| Hyperphosphorylated tau protein local | drug |
| IgG secondary antibody local | drug |
| Image Studio Lite 4.0 local | drug |
| induced pluripotent stem cells | drug |
| Inhibitory neuron local | cohort |
| ISF | drug |
| IWP-II local | drug |
| knock-in mice | cohort |
| knockout serum replacement | drug |
| KSR medium | drug |
| laminin | drug |
| LDLR | gene |
| LDN-193189 local | drug |
| LoxP-floxed apoE4 knock-in mice local | cohort |
| MAP2 | gene |
| Mapt | gene |
| matrigel | drug |
| Mature neurons local | cohort |
| medial ganglionic eminence | anatomy |
| medial ganglionic eminence cells local | phenotype |
| MGE cells local | cohort |
| mice | cohort |
| miPSC lines local | cohort |
| miPSCs local | cohort |
| Mixed neuronal culture local | cohort |
| Mouse AΞ² peptide local | phenotype |
| Mouse brain ISF local | anatomy |
| mouse iPSC-derived neurons local | cohort |
| mouse neurons local | cohort |
| mTeSR1 medium | drug |
| N2 supplement | drug |
| Nanog | gene |
| NEAA | drug |
| NES | gene |
| nestin | gene |
| Neural Differentiation Medium local | drug |
| Neural Progenitor Medium local | drug |
| neural stem cells | cohort |
| neurobasal medium | drug |
| neurofibrillary tangles | phenotype |
| NEUROG2 | gene |
| neuronal activity | phenotype |
| neuronal cultures | cohort |
| Neuronal hyperactivity local | phenotype |
| neurons | phenotype |
| neurotoxic fragments local | drug |
| NKX2-1 | gene |
| NOD-SCID mice | cohort |
| nonessential amino acids local | drug |
| NP-40 | drug |
| Nploc4 | gene |
| Odyssey Blocking Buffer local | drug |
| Odyssey CLx Imaging System local | drug |
| oligo dT local | drug |
| paraformaldehyde | drug |
| parental apoE4/4 hiPSCs local | cohort |
| Pax6 | gene |
| PD0325901 | drug |
| penicillin/streptomycin | drug |
| PH002 local | drug |
| PHF1 local | gene |
| PHF1 antibody local | drug |
| Phosphatase inhibitor cocktail 1 local | drug |
| Phosphatase inhibitor cocktail 2 local | drug |
| phosphorylated tau local | phenotype |
| Phusion High Fidelity DNA Polymerase local | drug |
| pilot cohort local | cohort |
| pluripotency genes local | gene |
| pmaxGFP vector local | drug |
| poly-l-ornithine | drug |
| postmortem human brain tissues local | drug |
| POU5F1 | gene |
| protease inhibitor cocktail | drug |
| PS1 | gene |
| p-tau | drug |
| p-tau local | phenotype |
| p-tau levels local | phenotype |
| P-tau levels local | phenotype |
| p-tau mislocalization local | phenotype |
| p-tau-positive neurons local | phenotype |
| Pure excitatory neuronal culture local | cohort |
| Pure excitatory neurons local | cohort |
| Qiagen RNeasy mini kit local | drug |
| recombinant human APOE3 local | drug |
| recombinant human APOE4 local | drug |
| ROCKi local | drug |
| Rock inhibitor | drug |
| SAG | drug |
| SB431542 | drug |
| SDS | drug |
| small-molecule structure corrector local | drug |
| SNL feeders local | drug |
| sodium deoxycholate | drug |
| soluble APP local | drug |
| soluble APP-Ξ² antibody local | drug |
| Sox2 | gene |
| Spatial learning and memory impairment local | phenotype |
| SSEA4 local | phenotype |
| SU5402 local | drug |
| Subjects with different apoE genotypes local | cohort |
| SuperScript III First-Strand Synthesis System local | drug |
| Supplementary Figure 15 local | cohort |
| Tau-5 antibody local | drug |
| tau-mediated neurodegeneration local | phenotype |
| tauopathy model mice local | cohort |
| tau pathology | phenotype |
| tau phosphorylation | drug |
| Tbr1 | gene |
| Tbr1-positive glutamatergic neurons local | phenotype |
| teratoma | phenotype |
| TGF-Ξ² receptor local | gene |
| Th | gene |
| Thermo Fisher Scientific | drug |
| TH-positive neurons local | phenotype |
| total tau local | phenotype |
| TRA-1-60 | phenotype |
| TRA-1-81 | phenotype |
| transgenic mice | cohort |
| TUBB3 | gene |
| Tuj1 | drug |
| Tuj1 antibody local | drug |
| vGLUT local | gene |
| ZFN local | drug |
| Ξ²-secretase | drug |
| Ξ²-secretase inhibitor | drug |
| Ξ³-secretase | drug |
| Ξ³-secretase inhibitor | drug |
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In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? | 2018 | 29897633 |
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| APOE4 reprograms microglial lipid metabolism in Alzheimer's disease: Mechanisms and therapeutic implications. | Chen J et al. | β | 2026 | β |
| Epilepsy therapy beyond neurons: Unveiling astrocytes as cellular targets. | Chen Y et al. | β | 2026 | β |
| Generating LGE/CGE Organoids from Human Pluripotent Stem Cell-derived Brain Organoids Without External Signal Induction. | Zhu X et al. | β | 2026 | β |
| Identification of aryl hydrocarbon receptor as a functional target that enhances astrocytic ApoE secretion. | Donovan KW et al. | β | 2026 | β |
| Neuropsychiatric symptoms and apolipoprotein E genotypes in neurocognitive disorders. | Lozupone M et al. | β | 2026 | β |
| The proportion of Alzheimer's disease attributable to apolipoprotein E. | Williams DM et al. | β | 2026 | β |
| Alzheimer's disease patient brain extracts induce multiple pathologies in novel vascularized neuroimmune organoids for disease modeling and drug discovery. | Ji Y et al. | β | 2025 | β |
| An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models. | Wang P et al. | β | 2025 | β |
| APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids. | Meyer-Acosta KK et al. | β | 2025 | β |
| APOE Genotype Difference in the Biphasic Modulation of Amyloid-Ξ² Aggregation by Direct Binding and Lowering the Nucleation Barrier. | Song Z et al. | β | 2025 | β |
| APOE Lipoprotein Particles: Pathophysiology, Therapy, and the Crosstalk in Alzheimer's Disease and Cardiovascular Disease. | Liu C et al. | β | 2025 | β |
| APOE-Targeted Therapeutics for Alzheimer's Disease. | Yassine HN et al. | β | 2025 | β |
| Apolipoprotein E in Alzheimer's disease: molecular insights and therapeutic opportunities. | Belaidi AA et al. | β | 2025 | β |
| A single fibril study reveals that ApoE inhibits the elongation of AΞ²42 fibrils in an isoform-dependent manner. | Dasadhikari S et al. | β | 2025 | β |
| A targeted approach: Gene and RNA editing for neurodegenerative disease treatment. | Huang CW et al. | β | 2025 | β |
| Cell culture research in aging and Alzheimer's disease: The strategic use/reuse of untreated controls and savings people's tax dollars. | Kshirsagar S et al. | β | 2025 | β |
| Clinical Significance of APOE4 Genotyping: Potential for Personalized Therapy and Early Diagnosis of Alzheimer's Disease. | RajiΔ Bumber J et al. | β | 2025 | β |
| CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer's disease: progress and prospects. | Khan MS et al. | β | 2025 | β |
| Current Development of iPSC-Based Modeling in Neurodegenerative Diseases. | Guo X et al. | β | 2025 | β |
| Differential Effects of AΞ² Peptides on the Plasmin-Dependent Degradation of ApoE3 and ApoE4. | Kemeh MM et al. | β | 2025 | β |
| Discovery of Isobavachin, a Natural Flavonoid, as an Apolipoprotein E4 (ApoE4) Structure Corrector for Alzheimer's Disease. | Patil SP et al. | β | 2025 | β |
| Fluid biomarkers of vascular cognitive Impairment: From vascular pathophysiology to potential clinical applications. | Tao X et al. | β | 2025 | β |
| From genetic roots to recent advancements in gene therapy targeting amyloid beta in Alzheimer's disease. | Peyvand P et al. | β | 2025 | β |
| Gene and RNA Editing: Revolutionary Approaches to Treating Diseases. | Li JM et al. | β | 2025 | β |
| Intravenously injected hPSC-derived pericytes for Alzheimer disease: Neuroprotection and vascular repair via extracellular vesicles. | Liu Y et al. | β | 2025 | β |
| Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction. | Krogsaeter EK et al. | β | 2025 | β |
| Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model. | Rao A et al. | β | 2025 | β |
| Multi-functional role of apolipoprotein E in neurodegenerative diseases. | Islam S et al. | β | 2025 | β |
| Pleiotropic effects of APOE variants on a sleep-based adult epidemiological cohort. | MoysΓ©s-Oliveira M et al. | β | 2025 | β |
| Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype. | Shvetcov A et al. | β | 2025 | β |
| Role of apolipoprotein E4 in alzheimer's disease pathogenesis and emerging therapeutic strategies. | Natarajan S et al. | β | 2025 | β |
| Spatiotemporal Dynamics of Central Nervous System Diseases: Advancing Translational Neuropathology via Single-Cell and Spatial Multiomics. | Xia M et al. | β | 2025 | β |
| Suppressing DUSP16 overexpression induced by ELK1 promotes neural progenitor cell differentiation in mouse models of Alzheimer's disease. | Zhao H et al. | β | 2025 | β |
| Targeting protein misfolding in Alzheimer's disease: The emerging role of molecular chaperones. | Sharma A et al. | β | 2025 | β |
| The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies. | Chen Y et al. | β | 2025 | β |
| The Role of APOA-I in Alzheimer's Disease: Bridging Peripheral Tissues and the Central Nervous System. | Xie G et al. | β | 2025 | β |
| The Role of Genetic, Environmental, and Dietary Factors in Alzheimer's Disease: A Narrative Review. | MertaΕ B et al. | β | 2025 | β |
| Transethnic analysis identifies SORL1 variants and haplotypes protective against Alzheimer's disease. | Zhou X et al. | β | 2025 | β |
| Trends and challenges of AAV-delivered gene editing therapeutics for CNS disorders: Implications for neurodegenerative disease. | Kantor B et al. | β | 2025 | β |
| Unraveling APOE4's Role in Alzheimer's Disease: Pathologies and Therapeutic Strategies. | Tripathi S et al. | β | 2025 | β |
| Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease. | Li X et al. | β | 2025 | β |
| Value of blood neural cell-derived small extracellular vesicles in the diagnosis and prediction of Alzheimer's disease: A systematic review. | Pan W et al. | β | 2025 | β |
| Variable and interactive effects of Sex, APOE Ξ΅4 and TREM2 on the deposition of tau in entorhinal and neocortical regions. | Giorgio J et al. | β | 2025 | β |
| Vascular models of Alzheimer's disease: An overview of recent in vitro models of the blood-brain barrier. | Takeuchi LE et al. | β | 2025 | β |
| 27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression: A key target potentially linking zearalenone and cancer. | Ruan H et al. | β | 2024 | β |
| Alzheimer's Disease: A Suitable Case for Treatment with Precision Medicine? | Pauwels EKJ et al. | β | 2024 | β |
| Alzheimer's disease phenotype based upon the carrier status of the apolipoprotein E Ι4 allele. | Ji XY et al. | β | 2024 | β |
| APOE4/4 is linked to damaging lipid droplets in Alzheimer's diseaseΒ microglia. | Haney MS et al. | β | 2024 | β |
| APOE4 homozygosity is a new genetic form of Alzheimer's disease. | Xu Q et al. | β | 2024 | β |
| APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons. | Budny V et al. | β | 2024 | β |
| APOE4 is a Risk Factor and Potential Therapeutic Target for Alzheimer's Disease. | Ayyubova G | β | 2024 | β |
| ApoE maintains neuronal integrity via microRNA and H3K27me3-mediated repression. | Tan J et al. | β | 2024 | β |
| Application of CRISPR/Cas9 System in the Treatment of Alzheimer's Disease and Neurodegenerative Diseases. | Rahimi A et al. | β | 2024 | β |
| Association of Apolipoprotein E Gene Polymorphisms with Risk of Coronary Artery Disease in a Han Chinese Population at Middle and High Altitude in China | Zeng F et al. | β | 2024 | β |
| Bio-Nano Toolbox for Precision Alzheimer's Disease Gene Therapy. | Liu Y et al. | β | 2024 | β |
| Cell type-specific roles of APOE4 in Alzheimer disease. | Blumenfeld J et al. | β | 2024 | β |
| CRISPR/Cas9 Gene Editing: A Novel Approach Towards Alzheimer's Disease Treatment. | Tripathi S et al. | β | 2024 | β |
| Directed Differentiation of Neurons from Human iPSCs for Modeling Neurological Disorders. | Wang C et al. | β | 2024 | β |
| Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer's Disease Cell Model. | Patil SP et al. | β | 2024 | β |
| Experimental Cell Models for Investigating Neurodegenerative Diseases. | Evangelisti C et al. | β | 2024 | β |
| From aberrant neurodevelopment to neurodegeneration: Insights into the hub gene associated with autism and alzheimer's disease. | Fu Y et al. | β | 2024 | β |
| Human stem cell transplantation models of Alzheimer's disease. | Ifediora N et al. | β | 2024 | β |
| Identifying the earliest-occurring clinically targetable precursors of late-onset Alzheimer's disease. | Cohen BM et al. | β | 2024 | β |
| In and out: Benchmarking inΒ vitro, inΒ vivo, exΒ vivo, and xenografting approaches for an integrative brain disease modeling pipeline. | Pereira MF et al. | β | 2024 | β |
| iPSC-derived blood-brain barrier modeling reveals APOE isoform-dependent interactions with amyloid beta. | Ding Y et al. | β | 2024 | β |
| Library screening identifies commercial drugs as potential structure correctors of abnormal apolipoprotein A-I. | Gkolfinopoulou C et al. | β | 2024 | β |
| Matrix Remodeling Enzymes as Potential Fluid Biomarkers of Neurodegeneration in Alzheimer's Disease. | BaΕ‘iΔ J et al. | β | 2024 | β |
| Mesenchymal stem cell therapy for Alzheimer's disease: A novel therapeutic approach for neurodegenerative diseases. | Bhatt A et al. | β | 2024 | β |
| Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease. | Sun GG et al. | β | 2024 | β |
| Microglial apolipoprotein E particles contribute to neuronal senescence and synaptotoxicity. | Wang N et al. | β | 2024 | β |
| MicroRNAs: pioneering regulators in Alzheimer's disease pathogenesis, diagnosis, and therapy. | Li YB et al. | β | 2024 | β |
| Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming. | Sun Z et al. | β | 2024 | β |
| Multifaceted roles of APOE in Alzheimer disease. | Jackson RJ et al. | β | 2024 | β |
| Multi-omics Analyses Reveal Function of Apolipoprotein E in Alternative Splicing and Tumor Immune Microenvironment in Kidney Renal Clear Cell Carcinoma via Pan-cancer Analysis. | Leng X et al. | β | 2024 | β |
| New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease. | Cao Y et al. | β | 2024 | β |
| Novel Role of Pin1-Cis P-Tau-ApoE Axis in the Pathogenesis of Preeclampsia and Its Connection with Dementia. | Amabebe E et al. | β | 2024 | β |
| Prevalence of ApoE Alleles in a Spanish Population of Patients with a Clinical Diagnosis of Alzheimer's Disease: An Observational Case-Control Study. | Bello-Corral L et al. | β | 2024 | β |
| Promoting Alzheimer's disease research and therapy with stem cell technology. | Cao Z et al. | β | 2024 | β |
| Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease. | Western D et al. | β | 2024 | β |
| Rational correction of pathogenic conformational defects in HTRA1. | Beaufort N et al. | β | 2024 | β |
| Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. | Vance JM et al. | β | 2024 | β |
| Simple modeling of familial Alzheimer's disease using human pluripotent stem cell-derived cerebral organoid technology. | Choe MS et al. | β | 2024 | β |
| Synaptic vesicle glycoprotein 2Β A in serum is an ideal biomarker for early diagnosis of Alzheimer's disease. | Wang X et al. | β | 2024 | β |
| Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects. | Tong B et al. | β | 2024 | β |
| The Contributions of the Endolysosomal Compartment and Autophagy to APOEΙ4 Allele-Mediated Increase in Alzheimer's Disease Risk. | Asiamah EA et al. | β | 2024 | β |
| The role of <i>APOE</i> gene polymorphisms in lung adenocarcinoma susceptibility and lipid profile. | Bi H et al. | β | 2024 | β |
| Thy1-ApoE4/C/EBPΞ² double transgenic mice act as a sporadic model with Alzheimer's disease. | Qian Z et al. | β | 2024 | β |
| Ξ²-Amyloid species production and tau phosphorylation in iPSC-neurons with reference to neuropathologically characterized matched donor brains. | Oakley DH et al. | β | 2024 | β |
| A Function of Amyloid-Ξ² in Mediating Activity-Dependent Axon/Synapse Competition May Unify Its Roles in Brain Physiology and Pathology. | Huang Z | β | 2023 | β |
| Altered ubiquitin signaling induces Alzheimer's disease-like hallmarks in a three-dimensional human neural cell culture model. | Maniv I et al. | β | 2023 | β |
| Alzheimer's Disease and Its Possible Evolutionary Origin: Hypothesis. | Whitfield JF et al. | β | 2023 | β |
| Alzheimer's disease and synapse Loss: What can we learn from induced pluripotent stem Cells? | Rodriguez-Jimenez FJ et al. | β | 2023 | β |
| Apoe4 and Alzheimer's Disease Pathogenesis-Mitochondrial Deregulation and Targeted Therapeutic Strategies. | Pires M et al. | β | 2023 | β |
| APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release. | Koutsodendris N et al. | β | 2023 | β |
| APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids. | Zhao J et al. | β | 2023 | β |
| APOE effects on regional tau in preclinical Alzheimer's disease. | Young CB et al. | β | 2023 | β |
| APOEΞ΅4 potentiates amyloid Ξ² effects on longitudinal tau pathology. | Ferrari-Souza JP et al. | β | 2023 | β |
| Apolipoprotein E in lipid metabolism and neurodegenerative disease. | Yang LG et al. | β | 2023 | β |
| Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model. | Davies C et al. | β | 2023 | β |
| Apolipoprotein E Ξ΅4 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKCΞ΅ mislocalization in cholinergic neuronal cells. | Piccarducci R et al. | β | 2023 | β |
| Astrocytic response mediated by the CLU risk allele inhibits OPC proliferation and myelination in a human iPSC model. | Liu Z et al. | β | 2023 | β |
| CDiP technology for reverse engineering of sporadic Alzheimer's disease. | Kondo T et al. | β | 2023 | β |
| Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer's disease risk gene SORL1. | Lee H et al. | β | 2023 | β |
| Cholesterol-dependent amyloid Ξ² production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol. | Rudajev V et al. | β | 2023 | β |
| COVID-19 and Alzheimer's Disease: Neuroinflammation, Oxidative Stress, Ferroptosis, and Mechanisms Involved. | Pomilio AB et al. | β | 2023 | β |
| Cross interactions between Apolipoprotein E and amyloid proteins in neurodegenerative diseases. | Loch RA et al. | β | 2023 | β |
| Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. | Nemergut M et al. | β | 2023 | β |
| FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPΞ²/Ξ΄-secretase in female mice. | Xiong J et al. | β | 2023 | β |
| GABAergic signaling abnormalities in a novel CLU mutation Alzheimer's disease mouse model. | Chen C et al. | β | 2023 | β |
| Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons and Glia for the Elucidation of Pathogenic Mechanisms in Alzheimer's Disease. | Young JE et al. | β | 2023 | β |
| Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy. | Bershteyn M et al. | β | 2023 | β |
| Implication of tau propagation on neurodegeneration in Alzheimer's disease. | Lamontagne-Kam D et al. | β | 2023 | β |
| [iPS cell technologies toward overcoming neurological diseases]. | Kimura T et al. | β | 2023 | β |
| Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise. | Yin F | β | 2023 | β |
| Microglia in Alzheimer's disease: pathogenesis, mechanisms, and therapeutic potentials. | Miao J et al. | β | 2023 | β |
| MicroRNAs in Extracellular Vesicles of Alzheimer's Disease. | Li W et al. | β | 2023 | β |
| Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview. | Alshial EE et al. | β | 2023 | β |
| Molecular Insights into Cell Type-specific Roles in Alzheimer's Disease: Human Induced Pluripotent Stem Cell-based Disease Modelling. | Qu W et al. | β | 2023 | β |
| Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. | Koutsodendris N et al. | β | 2023 | β |
| Quantitative Proteomic Analysis Reveals apoE4-Dependent Phosphorylation of the Actin-Regulating Protein VASP. | Cakir Z et al. | β | 2023 | β |
| Relationship of Apolipoprotein E with Alzheimer's Disease and Other Neurological Disorders: An Updated Review. | Lou T et al. | β | 2023 | β |
| Reprogramming iPSCs to study age-related diseases: Models, therapeutics, and clinical trials. | Esteves F et al. | β | 2023 | β |
| Roles of ApoE4 on the Pathogenesis in Alzheimer's Disease and the Potential Therapeutic Approaches. | Sun YY et al. | β | 2023 | β |
| Suppression of Wnt/Ξ²-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer's Disease. | Macyczko JR et al. | β | 2023 | β |
| The Adult Neurogenesis Theory of Alzheimer's Disease. | Abbate C | β | 2023 | β |
| The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. | Nelson MR et al. | β | 2023 | β |
| The Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimer's Disease. | Sahlgren Bendtsen KM et al. | β | 2023 | β |
| Therapeutic Potential of Nanomedicine in Management of Alzheimer's Disease and Glioma. | Anwar F et al. | β | 2023 | β |
| Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges. | Guerreiro S et al. | β | 2023 | β |
| Advances in Recapitulating Alzheimer's Disease Phenotypes Using Human Induced Pluripotent Stem Cell-Based In Vitro Models. | Hasan MF et al. | β | 2022 | β |
| A multi-hit hypothesis for an APOE4-dependent pathophysiological state. | Steele OG et al. | β | 2022 | β |
| A "multi-omics" analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice. | Barisano G et al. | β | 2022 | β |
| Amyloid Ξ², Tau, and Ξ±-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases. | Sengupta U et al. | β | 2022 | β |
| An insight into the iPSCs-derived two-dimensional culture and three-dimensional organoid models for neurodegenerative disorders. | Bhargava A et al. | β | 2022 | β |
| APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-ΞΊB activation. | Arnaud L et al. | β | 2022 | β |
| ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease. | Li Y et al. | β | 2022 | β |
| ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies. | Raulin AC et al. | β | 2022 | β |
| APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer's disease pathology and brain diseases. | FernΓ‘ndez-Calle R et al. | β | 2022 | β |
| APOE Ξ΅4-dependent effects on the early amyloid pathology in induced neuronsΒ of patients with Alzheimer's disease. | Kim H et al. | β | 2022 | β |
| Apolipoprotein E and Alzheimer's disease. | Troutwine BR et al. | β | 2022 | β |
| Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms. | Koutsodendris N et al. | β | 2022 | β |
| Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases. | Alagarsamy J et al. | β | 2022 | β |
| Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer's disease? | Vecchio FL et al. | β | 2022 | β |
| Association of apolipoprotein E epsilon 4 and cognitive impairment in adults living with human immunodeficiency virus: a meta-analysis. | Mu T et al. | β | 2022 | β |
| Building in vitro models of the brain to understand the role of <i>APOE</i> in Alzheimer's disease. | Pinals RL et al. | β | 2022 | β |
| Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. | Tcw J et al. | β | 2022 | β |
| Clinical Research Investigating Alzheimer's Disease in China: Current Status and Future Perspectives Toward Prevention. | Wang Q et al. | β | 2022 | β |
| CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics. | Sen T et al. | β | 2022 | β |
| CRISPR/Cas9 gene editing: New hope for Alzheimer's disease therapeutics. | Bhardwaj S et al. | β | 2022 | β |
| Culture Variabilities of Human iPSC-Derived Cerebral Organoids Are a Major Issue for the Modelling of Phenotypes Observed in Alzheimer's Disease. | HernΓ‘ndez D et al. | β | 2022 | β |
| Dissection of the polygenic architecture of neuronal AΞ² production using a large sample of individual iPSC lines derived from Alzheimer's disease patients. | Kondo T et al. | β | 2022 | β |
| Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia. | Yu Y et al. | β | 2022 | β |
| Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers. | Jansen IE et al. | β | 2022 | β |
| Human iPSC-Derived Neural Models for Studying Alzheimer's Disease: from Neural Stem Cells to Cerebral Organoids. | Barak M et al. | β | 2022 | β |
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