ROCK1 Is Associated with Alzheimer’s Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance

Abstract

Alzheimer’s disease (AD) is the most prevalent form of late-life dementia in the population, characterized by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1). In this study, we further analyze whether ROCK1 regulates the metabolism of amyloid precursor protein (APP). We show that ROCK1 is colocalized with mature amyloid-β (Aβ) plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aβ in a cell model of AD (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model). In vitro over-expression of ROCK1 leads to a decrease in Aβ secretion and an increase in the expression of autophagy-related molecules. ROCK1 interacts with Beclin1, an autophagy initiator, and enhances the intracellular accumulation of Aβ. Reciprocally, overexpression of APP/Aβ promotes ROCK1 expression. Our data suggest ROCK1 participates in regulating Aβ secretion, APP shedding and autophagosome accumulation, and that ROCK1, rather than other kinases, is more likely to be a targetable enzyme for AD therapy.

Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress

“…The in situ cell death detection kit (FITC) (Chemicon, Temecula, CA, USA) was used to detect apoptosis in the tissue following the manufacturer's instructionsas described previously [21]. Briefly, the sections were dewaxed and rehydrated by heating the slides at 60 °C.…”

Rho‐associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

“…Additionally, in brains of AD patients, ROCK1 immunoreactivity co‐localizes with the cores of mature Aβ plaques (Hu et al . ). Collectively these findings implicate a closely linked relationship between ROCKs and Aβ deposition/clearance.…”

“…Inhibition of both ROCK isoforms by fasudil achieved similar results in the APP/PS1 mouse model of AD (Yu et al 2016). In addition to Ab and APP processing, ROCK1 has been proposed as an initiator of Ab autophagy; in vitro over-expression of ROCK1 promotes internalization of Ab and increased formation of autophagosomes (Hu et al 2016). Additionally, in brains of AD patients, ROCK1 immunoreactivity co-localizes with the cores of mature Ab plaques (Hu et al 2016).…”

“…That being said, inhibition of either is sufficient to affect Ab processing in the brain (Herskowitz et al 2013;Henderson et al 2016). Additionally, in both rodent models and AD patients, both isoforms are elevated in the brain (Herskowitz et al 2013;Henderson et al 2016;Hu et al 2016) implicating that a non-specific strategy may be more effective. Tissue-specific bioavailability, safety, and timing Administration of ROCK1/ROCK2 inhibitors via peripheral routes have generally been successful in crossing the intact BBB and achieving the desired targets in the brain (Huentelman et al 2009;Hou et al 2012;Tatenhorst et al 2016).…”

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

“…Moreover, our results (Figs. 3B and 3C) showed that the diabetic pathophysiological factors could upregulate ROCK1 and 14-3-3σ which are associated with neurodegeneration [32, 33]. Thus it would be interesting to investigate whether ROCK1 or 14-3-3σ is a link between type 2 diabetes and Alzheimer's disease which shows an increased risk in type 2 diabetes [34].…”