Caspase-6 activity predicts lower episodic memory ability in aged individuals

Ramcharitar, Jasmine; Afonso, Veronica M.; Albrecht, Steffen; Bennett, David A.; LeBlanc, Andréa C.

doi:10.1016/j.neurobiolaging.2013.01.007

Cited by 37 publications

(54 citation statements)

References 36 publications

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“…Previously, a semiquantitative assessment correlated the amount of Casp6 activity in ERC and CA1 with lower performance in declarative memory. 6 The Casp6 activity measured with neoepitope anti-active Casp6 immunostaining correlated significantly with neoepitope TauDCasp6 immunostaining, and each immunostaining correlated similarly with a lower performance in cognitive abilities in the CA1 region of the hippocampus. Herein, a more in-depth quantitative analysis of the amount of TauDCasp6/mm 2 in the CA1 of 16 aged NCI cases (demographics and cognitive scores are in Table 1) showed that the level of Casp6 activity assessed with TauDCasp6 immunohistological staining correlated negatively with global cognitive scores (Spearman rank r ¼ À 0.615, P ¼ 0.011) and declarative EP (r ¼ À 0.639; P ¼ 0.008) and semantic memories (SEs: r ¼ À 0.562, P ¼ 0.023) (Figure 1d).…”

Section: Resultsmentioning

confidence: 85%

“…This could explain why removal of Ab in individuals with mild AD did not delay progression of the disease. 41 Although there is still considerable support for amyloid being a cause of AD, 42 there is also evidence to indicate that Casp6 can be upstream or parallel to Ab and NFT production: lack of correlation between Ab and memory performance despite a strong correlation with Casp6 and PHF-1 in aged hippocampi, 6 Casp6-dependent Ab production in human CNS primary neuron cultures, 15,16 Casp6-dependent, but Ab-independent, neuritic degeneration in APP-transfected human primary neurons, 14 and caspase activity leading to NFT in mice. 8 Targeting Casp6, in addition to Ab and NFT, may be required to efficiently prevent AD progression.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Furthermore, higher levels of Casp6 activity in the ERC and cornu ammonis 1 (CA1) region of NCI brains correlate with lower episodic memory (EP) performance, one of the types of memory also affected early in AD. 6 Active Casp6 induces several parallel degenerative pathways associated with AD neuropathology. First, Casp6 activity disrupts the neuronal cytoskeleton.…”

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confidence: 99%

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Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

et al. 2014

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Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops agedependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. Cell Death and Differentiation (2014) 21, 696-706; doi:10.1038/cdd.2013; published online 10 January 2014The underlying molecular pathway for neuronal degeneration and dysfunction in Alzheimer's disease (AD) remains unknown. Yet, the identification of critical events initiating neuronal degeneration could provide a novel therapeutic approach to stem the progressive dementia of AD. We propose that Caspase-6 (Casp6), a cysteinyl protease of the caspase family, has a critical role in AD neuronal degeneration and cognitive impairment. Casp6 activity is intimately associated with the neuritic plaques (NP), neurofibrillary tangles (NFT), and neuropil threads (NPT) of AD. 1 Casp6 activity is abundant in familial AD 2 and at all stages of sporadic AD. 3 Although no Casp6 activity is present in younger brains, 1 several aged non-cognitively impaired (NCI) brains show significant amounts of Casp6 activity in the entorhinal cortex (ERC), 3 the first area showing NFT pathology in AD according to Braak staging. 4,5 Furthermore, higher levels of Casp6 activity in the ERC and cornu ammonis 1 (CA1) region of NCI brains correlate with lower episodic memory (EP) performance, one of the types of memory also affected early in AD. 6 Active Casp6 induces several parallel degenerative pathways associated with AD neuropathology. First, Casp6 activity disrupts the neuronal cytoskeleton. Casp6 cleaves neuronal microtubule protein alpha-tubulin, microtubuleassociated protein Tau, and actin-regulating post-synaptic density proteins, Spinophilin, Drebrin, and Actinins. 7 In mouse, caspase activity precedes and leads to the formation of NFT-like aggregation. 8 Casp6 activity is involved in axonal degeneration of mouse PNS neurons via amyloid precursor protein (APP) interaction with death receptor 6 9 and in nerve growth factor (NGF)-deprived dorsal root ganglion neurons. 10 Furthermore, Casp6-dependent axonal degeneration i...

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Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

et al. 2014

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“…Of note, experiments in hippocampal primary cultures demonstrate that STK4, an homolog of STK3, is phosphorylated upon oxidative stress by c-abl leading to the stabilization of the protein expression of STK4 and the STK4-FOXO mediated cell death (Xiao et al 2011). Moreover, CASP6 is activated in neurodegenerative diseases and its activity in the hippocampal CA1 region is sufficient to induce neuronal degeneration, inflammation and age-related memory impairment (LeBlanc et al 2014;Ramcharitar et al 2013;Graham, Ehrnhoefer, and Hayden 2011b;Wang et al 2015). Thus, the increase in mRNA expression of STK3 and CASP6, a protease that cleaves STK3, highlight a possible role for STK3 in the neurodegeneration process in AD and potentially other neurodegenerative diseases.…”

Section: Caspases Expression and Processing Of Stk3 In The Brainmentioning

confidence: 99%

“…Activation of caspases is observed in many physiological and pathological processes including Alzheimer disease, Huntington disease, stroke and aging (Broughton, Reutens, and Sobey 2009;Graham, Ehrnhoefer, and Hayden 2011a;LeBlanc 2013;Lee and Kim 2006;Pattison et al 2006;Snigdha et al 2012). The expression levels and activity of caspases during the aging process is organ and tissue specific.…”

Section: Introductionmentioning

confidence: 99%

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Lessard‐Beaudoin

Laroche

Loudghi

et al. 2016

Neurobiology of Aging

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Caspases and their substrates are key mediators of apoptosis and strongly implicated in various physiological processes. As the STK family is involved in apoptosis, and STK3 is a recently identified caspase-6 substrate, we assessed the expression and cleavage of STK3 in murine peripheral organs and brain regions during the aging process. We also assessed caspase-3, -6, -7 and -8 expression and activity in order to delineate potential mechanism(s) underlying the generation of the STK3 fragments observed, and their relation to the apoptotic pathway. We demonstrate for the first time the cleavage of STK3 by caspase-7 and show that STK3 protein levels globally increase throughout the organism with age. In contrast, caspase-3, -6, -7 and -8 expression and activity vary significantly amongst the different organs analyzed suggesting differential effects of aging on the apoptotic mechanism and/or non-apoptotic functions of caspases throughout the organism. These results further our understanding of the role of caspases and their substrates in the normal aging process and highlight a potential role for STK3 in neurodegeneration.3

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The Role of Neuronal NLRP1 Inflammasome in Alzheimer’s Disease: Bringing Neurons into the Neuroinflammation Game

et al. 2019

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The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling. The NLR family pyrin domain-containing 1 (NLRP1) inflammasome in the CNS is primarily expressed by pyramidal neurons and oligodendrocytes. NLRP1 is activated in response to amyloid-β (Aβ) aggregates and its activation subsequently cleaves caspase-1 into its active subunits. The activated caspase-1 proteolytically processes interleukin-1β and interleukin-18 (IL-1β and IL-18) into maturation whilst co-ordinately triggers caspase-6 which is responsible for apoptosis and axonal degeneration. In addition, caspase-1 activation also induces pyroptosis, an inflammatory form of programmed cell death. Studies in murine AD models indicate that the NLRP1 inflammasome is indeed upregulated in AD and neuronal death is observed leading to cognitive decline. However, the mechanism of NLRP1 inflammasome activation in AD is particularly elusive, given its structural and functional complexities. In this review, we examine the implications of the human NLRP1 inflammasome and its signalling pathways in driving neuroinflammation in AD.

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Caspase-6 activity predicts lower episodic memory ability in aged individuals

Cited by 37 publications

References 36 publications

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

The Role of Neuronal NLRP1 Inflammasome in Alzheimer’s Disease: Bringing Neurons into the Neuroinflammation Game

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