Research Paper Volume 12, Issue 12 pp 12142—12159
Enhanced autophagic retrograde axonal transport by dynein intermediate chain upregulation improves Aβ clearance and cognitive function in APP/PS1 double transgenic mice
- 1 Institute of Neuroscience, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
- 2 Key Laboratory for Biorheological Science and Technology of Ministry of Education, Chongqing University, Chongqing University Cancer Hospital, Chongqing 400044, China
- 3 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
- 4 Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
- 5 Department of Pathophysiology, Chongqing Medical University, Chongqing 400016, China
Received: January 19, 2020 Accepted: May 23, 2020 Published: June 24, 2020https://doi.org/10.18632/aging.103382
How to Cite
Copyright © 2020 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Autophagosome accumulation is observed in the distal axons of Alzheimer disease (AD) patients and AD animal models, suggesting that deficient retrograde transport and impaired autophagic clearance of beta-amyloid (A β) contribute to AD pathogenesis. Expression of the retrograde axonal transport-related protein dynein intermediate chain (DIC) is also reduced in AD patients, but the contributions of DIC to AD pathology remain elusive. This study investigated the effects of DIC expression levels on cognitive function, autophagosome axonal transport, and A β clearance in the APP/PS1 double transgenic mouse model of AD. Autophagic activity was enhanced in the hippocampus of young (3-month-old) AD mice, as evidenced by greater expression of autophagosome markers, lysosome markers, axonal transport motors (including DIC), and dynein regulatory proteins. The expression levels of autophagosome markers remained elevated, whereas those of autophagic and axonal transport proteins decreased progressively with age, accompanied by spatial learning and memory deficits, axonal autophagosome accumulation, and A β deposition. Knockdown of DIC exacerbated while overexpression improved axonal transport, autophagosome maturation, Aβ clearance, and spatial learning and memory in aged AD mice. Our study provides evidence that age-dependent failure of axonal autophagic flux contributes to AD-associated neuropathology and cognitive deficits, suggesting DIC as a potential therapeutic target for AD.
AD: Alzheimer’s disease; APP: Amyloid precursor protein; Aβ: β-amyloid protein; NFTs: Neurofibrillary tangles; RILP:: Rab7- interacting lysosomal protein); FYCO1: FYVE and coiled-coil protein; ORP1L: oxysterol-binding protein-related protein 1L; Dynactin: Dynamic Actin; LC3: Microtubule Associated Protein 1 Light Chain3, MAP1LC3B, MAP1A/1BLC3; P62: Sequestosome 1; DIC: Dynein Intermediate Chain; LAMP2: Lysosomal-associated membrane protein 2; CTSD: Cathepsin D; KIF5B: Kinesin family member 5B; P50: Dynacin2; P150: P150Glued; BCA: Bicinchoninic acid; HRP: Avidin-Horseradish Peroxidase; TEM: Transmission electron microscopy; N2a: Mouse Neuroblastoma 2a cell line; MWM: Morris water maze test; APP/PS1 double transgenic mice: APPswe/PSEN1dE9 (APP/PSI) transgenic Alzheimer’s disease model mice..