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1. Distinct Rab7-related Endosomal–Autophagic–Lysosomal Dysregulation Observed in Cortex and Hippocampus in APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease

Author

Li Ba, Xiao-Hua Chen, Yan-Lin Chen, Qing Nie, Zhi-Jun Li, Feng-Fei Ding, and Min Zhang

Subjects
Autophagy, Class III Phosphatidylinositol 3-Kinase Complex, Endocytosis, Neurodegeneration, Rab7, Medicine
Abstract

Background: Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer's disease (AD). Dysregulation of the endosomal–autophagic–lysosomal (EAL) pathway, which impairs amyloid precursor protein processing, is one of the earliest changes in AD. However, the precise role of EAL pathway in neurodegeneration remains unclear. This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction. Methods: We used 3-, 7-, and 12-month-old APPswe/PSEN1dE9 (APP/PS1) mice to model different stages of AD with age- and gender-matched wild-type littermates as controls (4–7 mice per group) and detected the changes of EAL markers, endosomal organizers Rab5 and Rab7, autophagosome marker LC3B, and lysosomal proteins Lamp1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis. To further explore the mechanism of EAL dysregulation in AD, components of the class III phosphatidylinositol 3-kinase (PI3KC3) complex, activators of Rab7 (Beclin1 and UVRAG), and the negative regulator of Rab7 (Rubicon) were also measured in this two brain regions. Results: In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly, EAL pathway, and related PI3KC3 members, UVRAG and Beclin1 were upregulated both in cortex and hippocampus (all P < 0.05). By the age of 12 months old, when abundant amyloid plaques formed, EAL markers, UVRAG, and Beclin1 were also upregulated in the cortex (all P < 0.05). However, Rab7 was decreased significantly (P = 0.0447), accompanied by a reduction of its activating PI3KC complex component Beclin1 (P = 0.0215) and enhancement of its inhibiting component Rubicon (P = 0.0055) in the hippocampus. Conclusions: Our study implies that EAL pathway, represented as Rab7 and its PI3KC3 regulators' expressions, showed temporal and spatial variation in brains at different stages of AD. It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases.

Published
2017
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2. Distinct Rab7-related Endosomal–Autophagic–Lysosomal Dysregulation Observed in Cortex and Hippocampus in APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease

Author

Zhi-jun Li, Min Zhang, Qing Nie, Xiao-Hua Chen, Yan-Lin Chen, Li Ba, and Feng-Fei Ding

Subjects
0301 basic medicine, Autophagosome, Male, Amyloid beta, Blotting, Western, Hippocampus, lcsh:Medicine, UVRAG, Mice, Transgenic, Biology, 03 medical and health sciences, Mice, Downregulation and upregulation, Alzheimer Disease, Class III Phosphatidylinositol 3-Kinase Complex, Rab7, medicine, Amyloid precursor protein, Autophagy, Animals, Neurodegeneration, Cerebral Cortex, lcsh:R, rab7 GTP-Binding Proteins, General Medicine, medicine.disease, Class III Phosphatidylinositol 3-Kinases, Immunohistochemistry, Endocytosis, Cell biology, Disease Models, Animal, 030104 developmental biology, rab GTP-Binding Proteins, biology.protein, Female, Original Article, Lysosomes
Abstract

Background: Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer’s disease (AD). Dysregulation of the endosomal–autophagic–lysosomal (EAL) pathway, which impairs amyloid precursor protein processing, is one of the earliest changes in AD. However, the precise role of EAL pathway in neurodegeneration remains unclear. This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction. Methods: We used 3-, 7-, and 12-month-old APPswe/PSEN1dE9 (APP/PS1) mice to model different stages of AD with age- and gender-matched wild-type littermates as controls (4–7 mice per group) and detected the changes of EAL markers, endosomal organizers Rab5 and Rab7, autophagosome marker LC3B, and lysosomal proteins Lamp1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis. To further explore the mechanism of EAL dysregulation in AD, components of the class III phosphatidylinositol 3-kinase (PI3KC3) complex, activators of Rab7 (Beclin1 and UVRAG), and the negative regulator of Rab7 (Rubicon) were also measured in this two brain regions. Results: In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly, EAL pathway, and related PI3KC3 members, UVRAG and Beclin1 were upregulated both in cortex and hippocampus (all P< 0.05). By the age of 12 months old, when abundant amyloid plaques formed, EAL markers, UVRAG, and Beclin1 were also upregulated in the cortex (all P< 0.05). However, Rab7 was decreased significantly (P = 0.0447), accompanied by a reduction of its activating PI3KC complex component Beclin1 (P = 0.0215) and enhancement of its inhibiting component Rubicon (P = 0.0055) in the hippocampus. Conclusions: Our study implies that EAL pathway, represented as Rab7 and its PI3KC3 regulators’ expressions, showed temporal and spatial variation in brains at different stages of AD. It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases. Key words: Autophagy; Class III Phosphatidylinositol 3-Kinase Complex; Endocytosis; Neurodegeneration; Rab7

Published
2017

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