RT Journal Article
SR Electronic
T1 Pharmacologic Inhibition of ROCK2 Suppresses Amyloid-β Production in an Alzheimer's Disease Mouse Model
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 19086
OP 19098
DO 10.1523/JNEUROSCI.2508-13.2013
VO 33
IS 49
A1 Jeremy H. Herskowitz
A1 Yangbo Feng
A1 Alexa L. Mattheyses
A1 Chadwick M. Hales
A1 Lenora A. Higginbotham
A1 Duc M. Duong
A1 Thomas J. Montine
A1 Juan C. Troncoso
A1 Madhav Thambisetty
A1 Nicholas T. Seyfried
A1 Allan I. Levey
A1 James J. Lah
YR 2013
UL http://www.jneurosci.org/content/33/49/19086.abstract
AB Alzheimer's disease (AD) is the leading cause of dementia and has no cure. Genetic, cell biological, and biochemical studies suggest that reducing amyloid-β (Aβ) production may serve as a rational therapeutic avenue to delay or prevent AD progression. Inhibition of RhoA, a Rho GTPase family member, is proposed to curb Aβ production. However, a barrier to this hypothesis has been the limited understanding of how the principal downstream effectors of RhoA, Rho-associated, coiled-coil containing protein kinase (ROCK) 1 and ROCK2, modulate Aβ generation. Here, we report that ROCK1 knockdown increased endogenous human Aβ production, whereas ROCK2 knockdown decreased Aβ levels. Inhibition of ROCK2 kinase activity, using an isoform-selective small molecule (SR3677), suppressed β-site APP cleaving enzyme 1 (BACE1) enzymatic action and diminished production of Aβ in AD mouse brain. Immunofluorescence and confocal microscopy analyses revealed that SR3677 alters BACE1 endocytic distribution and promotes amyloid precursor protein (APP) traffic to lysosomes. Moreover, SR3677 blocked ROCK2 phosphorylation of APP at threonine 654 (T654); in neurons, T654 was critical for APP processing to Aβ. These observations suggest that ROCK2 inhibition reduces Aβ levels through independent mechanisms. Finally, ROCK2 protein levels were increased in asymptomatic AD, mild cognitive impairment, and AD brains, demonstrating that ROCK2 levels change in the earliest stages of AD and remain elevated throughout disease progression. Collectively, these findings highlight ROCK2 as a mechanism-based therapeutic target to combat Aβ production in AD.