Calpain Inhibitor A-705253 Mitigates Alzheimer's Disease–Like Pathology and Cognitive Decline in Aged 3xTgAD Mice

Medeiros, Rodrigo; Kitazawa, Masashi; Chabrier, Meredith A.; Cheng, David; Baglietto‐Vargas, David; Kling, Andreas; Moeller, Achim; Green, Kim N.; LaFerla, Frank M.

doi:10.1016/j.ajpath.2012.04.020

Cited by 77 publications

(71 citation statements)

References 47 publications

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“…In subarachnoid hemorrhage, calpain inhibition reduced behavioral deficits and BBB permeability (44). Similarly, calpain inhibition has been found to be protective against neuropathology associated with Alzheimer's disease, Parkinson's disease and conditions, such as lissencephaly (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Alluri

Grimsley²,

Shaji

et al. 2016

Journal of Biological Chemistry

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Edited by Paul FraserBlood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability followed by brain edema are hallmark features of several brain pathologies, including traumatic brain injuries (TBI). Recent studies indicate that pro-inflammatory cytokine interleukin-1␤ (IL-1␤) that is upregulated following traumatic injuries also promotes BBB dysfunction and hyperpermeability, but the underlying mechanisms are not clearly known. The objective of this study was to determine the role of calpains in mediating BBB dysfunction and hyperpermeability and to test the effect of calpain inhibition on the BBB following traumatic insults to the brain. In these studies, rat brain microvascular endothelial cell monolayers exposed to calpain inhibitors (calpain inhibitor III and calpastatin) or transfected with calpain-1 siRNA demonstrated attenuation of IL-1␤-induced monolayer hyperpermeability. Calpain inhibition led to protection against IL-1␤-induced loss of zonula occludens-1 (ZO-1) at the tight junctions and alterations in F-actin cytoskeletal assembly. IL-1␤ treatment had no effect on ZO-1 gene (tjp1) or protein expression. Calpain inhibition via calpain inhibitor III and calpastatin decreased IL-1␤-induced calpain activity significantly (p < 0.05). IL-1␤ had no detectable effect on intracellular calcium mobilization or endothelial cell viability. Furthermore, calpain inhibition preserved BBB integrity/permeability in a mouse controlled cortical impact model of TBI when studied using Evans blue assay and intravital microscopy. These studies demonstrate that calpain-1 acts as a mediator of IL-1␤-induced loss of BBB integrity and permeability by altering tight junction integrity, promoting the displacement of ZO-1, and disorganization of cytoskeletal assembly. IL-1␤-mediated alterations in permeability are neither due to the changes in ZO-1 expression nor cell viability. Calpain inhibition has beneficial effects against TBI-induced BBB hyperpermeability.The blood-brain barrier (BBB) 2 plays an important role in maintaining the homeostasis of the brain. Blood-brain barrier breakdown and the associated hyperpermeability are hallmark features of several brain pathologies and injuries. The BBB is mainly composed of the cerebral endothelial cells and the tight junctions (TJs) between them (1). TJs between the neighboring endothelial cells include transmembrane TJs, i.e. occludin, claudins, junctional adhesion molecules, etc., and membranebound TJs, i.e. zonula occludens (1). Zonula occludens play an important role in regulating BBB permeability by binding to both transmembrane tight junctions and actin cytoskeleton intracellularly (2). Various mediators of inflammation are shown to modulate BBB breakdown and permeability in a variety of pathologies (3). Blood-brain barrier breakdown and the associated hyperpermeability is the leading cause of brain edema and elevated intracranial pressure followed by decreased perfusion pressure leading to poor clinical outcomes in traumatic brain injury (TBI) (4).I...

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Section: Discussionmentioning

confidence: 99%

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Alluri

Grimsley²,

Shaji

et al. 2016

Journal of Biological Chemistry

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“…Hyperactivation of calpains has been detected early in AD in response to excitotoxicity, A␤ toxicity, and other forms of calcium injury (Bartus, 1997). Moreover, calpain-active cdk5 and ERK1/2 kinases can phosphorylate tau and induce myriad downstream tau-dependent and -independent pathogenic effects, including impairments of synaptic plasticity and cognition (Medeiros et al, 2012). Activated calpains are associated with tau aggregates in AD and other tauopathies and are not present on inclusions formed by several other pathogenic proteins (Adamec et al, 2002), suggesting a particularly important relationship of calpains to tauopathies among various proteinopathies.…”

Section: Introductionmentioning

confidence: 99%

“…Calpains, a family of calcium-dependent cysteine proteases, have been implicated in tauopathy development and neurodegeneration in AD (Nixon et al, 1994;Shea, 1997;Patrick et al, 1999;Rao et al, 2008), but its role in FTDP models in vivo is not known. Most calpain in cells is latent, and its activity is regulated by local calcium levels, phosphorylation, and reversible association with membranes or calpastatin (CAST; Wang and Yuen, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Synthetic inhibitors of calpains are neuroprotective in calcium injury (McCollum et al, 2006) and in mouse models of AD (Trinchese et al, 2008;Medeiros et al, 2012), but they lack specificity. CAST is the only specific endogenous inhibitor of calpains and a suicide inhibitor of calpain (Nagao et al, 1994), that is depleted in AD brain (Rao et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice

Rao

McBrayer

Campbell

et al. 2014

Journal of Neuroscience

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Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states.

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“…Another orally active and very promising compound is A-705253, a benzoylalanine-derived ketoamide that is under intense scrutiny and characterization. A-705253 proved to be active in the prevention of both tau phosphorylation and cleavage [174,175], and it is active in the 3xTgAD mouse model rescuing memory defects, reducing levels of BACE enzyme and Aβ deposits, decreasing overall neuroinflammation [174,176]. Taken together, these data suggest that calpain inhibition might be an efficient and reliable target for AD therapy.…”

Section: Calpainsmentioning

confidence: 63%

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

et al. 2015

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Therapeutic attempts to cure Alzheimer's disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. In this review, we will summarize literature that investigates 5 possible therapeutic pathways for rescuing synaptic dysfunction in AD: 4 enzymatic pathways that lead to CREB phosphorylation (the cyclic adenosine monophosphate cascade, the serine/threonine kinases extracellular regulated kinases 1 and 2, the nitric oxide cascade, and the calpains), as well as histone acetyltransferases and histone deacetylases (2 enzymes that regulate the histone acetylation necessary for gene transcription).

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Calpain Inhibitor A-705253 Mitigates Alzheimer's Disease–Like Pathology and Cognitive Decline in Aged 3xTgAD Mice

Cited by 77 publications

References 47 publications

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

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