APOE3 Christchurch modulates ß-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated ß-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.

APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation.

INTRODUCTION: We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs). METHODS: We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions. RESULTS: We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.

Lasting metabolic effect of a high-fructose diet on global cerebral ischemia.

Introduction: Obesity is a public health problem that is associated with cerebrovascular diseases, such as ischemic stroke. The coexistence of obesity with cerebral ischemia has been suggested to be considerably detrimental to the neurological system. Objective: Hence, in this study, we evaluated the long-term effects of a 20% high fructose diet (HFD) and global cerebral ischemia on neurological, cognitive and emotional performance in three-month-old male Wistar rats. Results: Our results demonstrated that fructose intake led to increases in body weight and blood glucose, as well as reduced insulin sensitivity. The co-morbidity of fructose intake and cerebral ischemia resulted to hyperlipidemia, as well as increases in liver and adipocyte damage, which worsened neurological performance and resulted in alterations in learning and emotional skills at two weeks post-ischemia. No significant biochemical changes in autophagy and plasticity markers at the late stage of ischemia were observed. Conclusion: These results suggested that obesity causes a lasting effect on metabolic disorders that can contribute to increased neurological impairment after cerebral ischemia.