Citations

Abstract In Alzheimer’s disease (AD), tau pathology arises in entorhinal cortex layer II (ECII) and advances through defined hippocampal circuits to CA1 and connected neocortical regions, yet the determinants of this hierarchical spread remain unclear. We previously established a circuit-defined propagation model by expressing Cre-inducible human P301L 2N4R tau selectively in Wolframin-1 (Wfs1) + ECII neurons using AAV-FLEX-Tau P301L in Wfs1-Cre mice. Here, to test how amyloid-β (Aβ) and human tau background shape propagation, we generated human MAPT knock-in Wfs1 mice and APP NL-G-F / MAPT double knock-in Wfs1 mice (T-Wfs1 and AT-Wfs1) and induced ECII-restricted Tau P301L expression. Three months after injection, phosphorylated or misfolded tau-positive neurons were enriched in proximal CA1 in Wfs1 and T-Wfs1 mice, resembling primary age-related tauopathy, whereas AT-Wfs1 mice showed preferential accumulation near the CA1/subiculum (Sub) boundary, consistent with an AD-like pattern. In T-Wfs1 and AT-Wfs1 mice, tau spread extended through Sub to neocortical regions, and phosphorylated tau accumulated predominantly in excitatory rather than inhibitory neurons. Electrophysiological analyses revealed increased spontaneous neuronal firing and impaired GABAergic transmission in the CA1/Sub boundary and neocortical areas in T-Wfs1 and AT-Wfs1 mice, indicative of impaired GABAergic input and enhanced neuronal excitability in these regions. Together, these data indicate that human MAPT and Aβ pathology shift the circuit topography of tau propagation and are associated with early network dysfunction, supporting a synergistic interaction that promotes AD-like spread and synaptic imbalance.

Abstract Hepatocellular carcinoma (HCC) located in the caudate lobe (caudate HCC) is rare; however, patients with this type of tumour have poorer prognoses than those with HCC in other segments. Despite many published reports on the clinical usefulness of proton beam therapy (PBT) for HCC, data on the clinical outcomes of patients undergoing PBT for caudate HCC remain scarce. Therefore, the present study aimed to investigate the outcomes of this group of patients. Thirty patients with caudate HCC who underwent definitive PBT between February 2002 and February 2014 were retrospectively analysed. The total irradiation doses ranged from 55 to 77 (median 72.6) Gy relative biological dose. The median follow-up period was 37.5 (range, 3.0–152.0) months. The overall survival (OS) rates at one, three and five years were 86.6%, 62.8% and 46.1%, respectively. According to univariate and multivariate analyses, Child-Pugh A (P < 0.01), having a single tumour (P = 0.02) and a low serum alpha-fetoprotein level (AFP; P < 0.01) were significant factors predicting longer survival. The local control (LC) rates at one, three and five years were 100%, 85.9% and 85.9%, respectively, while the corresponding progression-free survival (PFS) rates were 65%, 27.5% and 22%, respectively. No grade 3 or worse adverse events were observed. PBT is effective and safe for the treatment of caudate HCC, and should therefore be considered a feasible option for intervention in patients with this disease.

Abstract BackgroundHepatocellular carcinoma (HCC) located in the caudate lobe (caudate HCC) is rare; however, patients with this type of tumour have poorer prognoses than do those with HCC in other segments. Despite many published reports on the clinical usefulness of proton beam therapy (PBT) for HCC, data on the clinical outcomes of patients undergoing PBT for caudate HCC remain scare. Therefore, the present study aimed to investigate the outcomes of this group of patients.MethodsThirty patients with caudate HCC who underwent definitive PBT between February 2001 and February 2014 were retrospectively analysed. The total irradiation doses ranged from 55 to 77 (median 72.6) Gy relative biological dose.ResultsThe median follow-up period was 37.5 (range, 3.0–152.0) months. The overall survival rates at 1, 3, and 5 years were 86.6%, 62.8%, and 46.1%, respectively. According to univariate and multivariate analyses, Child-Pugh A (P < 0.01), having a single tumour (P = 0.02), and a low serum alpha-fetoprotein level (P < 0.01) were significant factors predicting longer survival. The local control rates at 1, 3, and 5 years were 100.0%, 85.9%, and 85.9%, respectively, while the corresponding progression-free survival rates were 65.0%, 27.5%, and 22.0%, respectively. No grade 3 or worse adverse events were observed.ConclusionsPBT is effective and safe for the treatment of caudate HCC, and should therefore be considered a feasible option for intervention in patients with this disease.

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to App NL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.