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Distinct Rab7-related Endosomal-Autophagic-Lysosomal Dysregulation Observed in Cortex and Hippocampus in APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease.
- Source :
-
Chinese medical journal [Chin Med J (Engl)] 2017 Dec 20; Vol. 130 (24), pp. 2941-2950. - Publication Year :
- 2017
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Alzheimer Disease physiopathology
Animals
Autophagy physiology
Blotting, Western
Class III Phosphatidylinositol 3-Kinases metabolism
Disease Models, Animal
Endocytosis physiology
Female
Immunohistochemistry
Lysosomes metabolism
Male
Mice
Mice, Transgenic
rab7 GTP-Binding Proteins
Alzheimer Disease metabolism
Cerebral Cortex metabolism
Cerebral Cortex pathology
Hippocampus metabolism
Hippocampus pathology
rab GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2542-5641
- Volume :
- 130
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Chinese medical journal
- Publication Type :
- Academic Journal
- Accession number :
- 29237927
- Full Text :
- https://doi.org/10.4103/0366-6999.220311