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Abstract
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.
Highlights
Macroautophagy, or autophagy, maintains cell viability, under stress, by recycling the constituent components of damaged macromolecules and organelles through a specific autophagic vesicle– lysosome degradation pathway [1,2,3,4]
We examined the dynamics of axon transport and the associations with autophagic β-amyloid protein (Aβ) clearance and cognitive function in Amyloid precursor protein (APP)/PS1 double transgenic Alzheimer disease (AD) model mice
Both patients with AD and PS1/APP double transgenic mice exhibit large numbers of immature autophagosomes [21, 25], suggesting that protein accumulation in AD may result from disrupted autophagy
Summary
Macroautophagy, or autophagy, maintains cell viability, under stress, by recycling the constituent components of damaged macromolecules and organelles through a specific autophagic vesicle– lysosome degradation pathway [1,2,3,4]. Nascent autophagic vesicles (autophagosomes) are mainly formed in distal axons and require longdistance retrograde transport to merge with degradative www.aging-us.com lysosomes located near the cell body for efficient recycling [5,6,7]. This dynamic process, termed autophagic flux, is essential to prevent the accumulation of damaged molecules and organelles with age [8]. Many of these accumulated molecules are cytotoxic, such as the Alzheimer disease (AD)-associated protein beta-amyloid (Aβ) [16, 17]
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