Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model.

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aß and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.

N-Cadherin-Mediated Activation of PI3K/Akt-GSK-3ß Signaling Attenuates Nucleus Pulposus Cell Apoptosis Under High-Magnitude Compression.

BACKGROUND/AIMS: Mechanical overloading-induced nucleus pulposus (NP) apoptosis plays an important role in the pathogenesis of intervertebral disc degeneration. N-cadherin (N-CDH)-mediated signaling preserves normal NP cell phenotype. This study aims to investigate the effects of N-CDH on NP cell apoptosis under high-magnitude compression and the underlying mechanism behind this process. METHODS: Rat NP cells seeded on scaffold were perfusion-cultured using a self-developed perfusion bioreactor for 5 days and experienced different magnitudes (2% and 20% compressive deformation, respectively) of compression at a frequency of 1.0 Hz for 4 hours once per day. The un-loaded NP cells were used as controls. Lentivirus-mediated N-CDH overexpression and inhibitor LY294002 were used to further investigate the role of N-CDH and PI3K/Akt pathway under high-magnitude compression, respectively. NP cell apoptosis was evaluated by caspase-3 activity measured using a commercial kit, flow cytometry, and expression of apoptosis-related molecules analyzed by real-time PCR and western blotting assays. RESULTS: High-magnitude compression significantly increased apoptotic NP cells, caspase-3 activity and expression of pro-apoptotic molecules (Bax and caspase-3/cleaved caspase-3), but decreased expression of anti-apoptotic molecule (Bcl-2). High-magnitude compression decreased expression of N-CDH, p-Akt and p-GSK-3ß. However, N-CDH overexpression attenuated NP cell apoptosis and increased expression of p-Akt and p-GSK-3ß under high-magnitude compression. Further analysis showed that inhibition of the PI3K/Akt pathway suppressed NP cell apoptosis and decreased expression of p-GSK-3ß, but had no significant effects on N-CDH expression under high-magnitude compression. CONCLUSION: N-CDH can attenuate NP cell apoptosis through activating the PI3K/Akt-GSK-3ß signaling under high-magnitude compression.

Different Surface Electromyography of Propagated Sensation along Meridians Produced by Acupuncturing Quchi Acupoint (LI11) or Control Points.

This study investigated the propagated sensation along meridians (PSM) produced respectively by acupuncture at a specific acupoint of right-side Quchi (LI11), a nonacupoint on meridian (control meridian point), and neither meridian nor acupoint (control point). All the stimulated points were on the right brachioradialis along the large intestine meridian of hand Yangming. Surface electromyography (sEMG) was used to reflect the activity of the brachioradialis along the large intestine meridian of hand Yangming. The PSM rate of LI11 (59.21%) and the control meridian point (53.95%) were significantly higher than the control point (38.16%) (P < 0.05). After acupuncture, the brachioradialis sEMG amplitude was 5.08 ± 2.93 uV at LI11, 3.08 ± 1.18 uV at the control point, and 2.77 ± 1.36 uV at the control meridian point. The amplitude of LI11 was significantly higher than both the control meridian point and the control point (P < 0.05). When the sEMG activity of brachioradialis returned to the stable base line, brachioradialis sEMG duration at LI11 (265 ± 87.87 s) was significantly longer than that at the control meridian point (91.69 ± 42.98 s) and the control point (83.31 ± 32.76 s) (P < 0.05). In conclusion, acupuncture activated PSM at all points but showed an acupoint specificity at LI11 and a meridian specificity at the control meridian point.