Activation of Caspase-6 in Aging and Mild Cognitive Impairment

Albrecht, Steffen; Bourdeau, Martine; Bennett, David A.; Mufson, Elliott J.; Bhattacharjee, Meena; LeBlanc, Andréa C.

doi:10.2353/ajpath.2007.060974

Cited by 145 publications

(182 citation statements)

References 27 publications

Supporting

Mentioning

169

Contrasting

Order By: Relevance

“…Caspase-6 is activated in brain tissue from pre-symptomatic individuals carrying the HD mutation and in individuals with only mild cognitive impairment that could progress into AD, supporting the idea of caspase activation as an early event in the pathogenesis of neurodegenerative disease 89,90 . These findings are paralleled by results that show the aberrant cleavage of caspase-6 substrates in brain tissue from patients suffering from HD or AD [90][91][92] .…”

Section: Preventing Caspase-6 Cleavage Is Beneficial In Ad and Hdmentioning

confidence: 68%

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Section: Supplementary Materialsmentioning

confidence: 99%

See 1 more Smart Citation

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

View full text Add to dashboard Cite

Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

show abstract

Section: Preventing Caspase-6 Cleavage Is Beneficial In Ad and Hdmentioning

confidence: 68%

Section: Supplementary Materialsmentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

View full text Add to dashboard Cite

show abstract

“…We have previously shown that the activation of the APP-dependent signaling targeted CBP to a caspase-6 degradation in primary cortical neuron cultures [76]. Notably, caspase-6 activity was highlighted in neurofibrillary tangles of AD brain patients [149][150][151]. Thus, the caspase 6-dependent degradation of CBP in AD, leading to an acetyltransferase loss in diseased neurons, has been hypothesized, suggesting HAT activation as an interesting strategy in AD.…”

Section: Ad and Related Diseasesmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

View full text Add to dashboard Cite

The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

show abstract

“…Unfortunately, not much is known about apoptotic processes with respect to MCI to date. However, one recent study ascertained that the effector caspase-6 was intimately linked to pathological hallmarks of AD in the hippocampus of persons with all stages of AD, including MCI and NCI (severely aged cognitively normal) (Albrecht et al, 2007). The present study investigated the hypothesis that PtdSer asymmetry is significantly altered in the inferior parietal lobule (IPL) of subjects with MCI and AD, which suggests that increased production of lipid peroxidation products (Butterfield et al, 2006a) and levels of apoptotic proteins may work together to affect PtdSer asymmetry even in MCI, arguably the earliest form of AD.…”

Section: Introductionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

View full text Add to dashboard Cite

Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

show abstract

Activation of Caspase-6 in Aging and Mild Cognitive Impairment

Cited by 145 publications

References 27 publications

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Contact Info

Product

Resources

About