Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice

Abstract

Caspases play critical roles in Alzheimer’s disease (AD) pathogenesis. Here we show that caspase-2 is required for the cognitive decline seen in hAPP transgenic mice (J20). The age-related changes in behavior and dendritic spine density observed in these mice are absent when they lack caspase-2, in spite of similar levels of Aβ deposition and inflammation. A similar degree of protection is observed in cultured hippocampal neurons lacking caspase-2, which are immune to the synaptotoxic effects of Aβ. Our studies suggest that caspase-2 is a critical mediator in the activation of the RhoA/ROCK-II signaling pathway, leading to the collapse of dendritic spines. We propose that this is controlled by an inactive caspase-2/RhoA/ROCK-II complex localized in dendrites, which dissociates in the presence of Aβ, allowing for their activation and entry in the spine. These findings directly implicate caspase-2 as key driver of synaptic dysfunction in AD and offer novel therapeutic targets.

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…At 12-18 months of age, these mice have also been reported to have significantly increased RhoA levels and decreased Rac1 levels in the brain [31]. Our recent studies in the hAPP J20 (Swedish and Indiana mutations) AD mouse model show a strong correlation between dendritic spine loss and behavioral deficits with a significant increase in RhoA activity [32]. In vitro studies in cultured cells also reflect these changes.…”

“…In vitro studies in cultured cells also reflect these changes. Aβ oligomers trigger a significant increase in RhoA activity in both SY5Y cells and in cultured hippocampal neurons [31][32][33][34]. Cdc42 and Rac1 levels have been reported to be elevated in select neuronal populations in AD brains compared with age-matched controls and have been proposed to perhaps play a role in activating cell cycle-related genes [35].…”

Old, new and emerging functions of caspases

“…This was attributed to an important role for caspse-2 in controlling dendrite spine density. 200 Caspase-2 was found to activate the RhoA/ROCK-II signaling pathway, leading to collapse of dendritic spines.…”

Amyloid beta1-42 peptide regulates microtubule stability independently of tau

“…Deregulation of Rho GTPase signaling has been implicated in neurotoxicity by Ab (Chacon et al, 2011;Petratos et al, 2008;Pozueta et al, 2013). Alterations in actin dynamics is generally considered the mechanism by which Rho contributes to the collapse of dendritic spines and impairs synaptic transmission, all early events occurring in neurons exposed to Ab (Lambert et al, 1998;Lefort et al, 2012;Lesné et al, 2006;Nimmrich and Ebert, 2009;Shankar et al, 2007).…”

“…However, it is not known whether neurotoxicity might also derive from changes in MT dynamics and/or MT post-translational modifications induced by Rho activation through the action on its effector mDia1 (Goulimari et al, 2005;Palazzo et al, 2001a). In neurons, APP and caspase-2 can regulate RhoA activation, and cells lacking either APP or caspase-2 are completely immune to Ab synaptotoxicity (Pozueta et al, 2013;Troy et al, 2000). In addition, dimerization of cellsurface APP by cross-linking cell-surface APP with a divalent antibody is sufficient to mimic the toxic effects of Ab in neurons (Lefort et al, 2012;Rohn et al, 2000).…”