ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes.

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

Validity and Reliability of Functional Independence Measure for Children (WeeFIM) for Children With Cerebral Palsy.

Purpose: This study was conducted to verify the validity and reliability of the Functional Independence Measure for Children (WeeFIM) for children with cerebral palsy by verifying the construct validity, difficulty, suitability, and cultural differences using Rasch analysis. Methods: From May 1, 2015, to February 27, 2020, 105 children with cerebral palsy aged 6 months-95 months (7 years and 11 months old) from Hospital Y located in Korea were included. In WeeFIM, 18 items were divided into 3 areas: Self-care 8 items, Motor 5 items, and Cognition 5 items. Analysis and separation reliability were analyzed. Results: In the Self-care area, the Grooming item and in the Motor area, the Transfer (Tub, Shower) item were judged as inappropriate items, and the order of difficulty was arranged without excluding the unsuitable items. In Self-acre, the most difficult item was Bathing, the easiest items were Eating and Bladder management, and the separation reliability was .87, the most difficult item in Motor was Stair, and the easiest item was Locomotion, and the separation reliability was .99. In Cognition, the most difficult item was Problem Solving, the easiest item was Communication, and the separation reliability was .95. Conclusion: The reliability and validity of WeeFIM was verified for children with cerebral palsy by applying Rasch Analysis. In future research, it is thought that additional research should be conducted by dividing the children by age and type so that they can be generalized.