Proteolytic Cleavage of Polymeric Tau Protein by Caspase-3: Implications for Alzheimer Disease

Jarero-Basulto, Jose J.; Luna-Muñoz, José; Mena, Raúl; Krištofíková, Zdena; Řı́pová, Daniela; Perry, George; Binder, Lester I.; Garcı́a-Sierra, Francisco

doi:10.1097/nen.0000000000000013

Cited by 46 publications

(26 citation statements)

References 94 publications

(98 reference statements)

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“…Casp3 , which had the lowest physiogenomic score considering the results of physiological-genomic analysis in relation to AD [22], was examined in the present study for the association with generation of the pathologic Asp (421) truncation of tau in long-lasting fibrillary structures [23]. Only one SNP—located in exon 7 of the Casp3 gene—was predicted as a missense mutation, but was scored as “tolerated” by the Variant Effect Predictor tool.…”

Section: Resultsmentioning

confidence: 99%

“…Among the gene variants that are found in OXYS rats but not in WAG rats, nonsynonymous SNPs are located only in the genes Casp3 and Sorl1 . Casp3 is associated with generation of a pathologic Asp (421) truncation of tau in long-lasting fibrillary structures [23]. The SORL1 gene has been studied as a susceptibility factor for late-onset AD, but the potentially pathogenic SORL1 mutations are also found in patients with early-onset AD [24].…”

Section: Discussionmentioning

confidence: 99%

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Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats

et al. 2014

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The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ1–42 and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats

et al. 2014

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“…Such studies may open new horizons in the prevention of neurological injury after CPB. Protease inhibitors are among potential treatment strategy for Alzheimer's disease, which are characterized by enhanced protease levels and apoE degradation products (19). Future studies with protease inhibitors and apoE structural modifiers may offer potential treatment alternatives to the near orphan status of drug development in the prevention of neurological injury after CPB in children.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E Levels in Pediatric Patients Undergoing Cardiopulmonary Bypass

et al. 2015

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Apolipoprotein E (apoE) may play a critical role in modulating the response to neurological injury after cardiopulmonary bypass (CPB) in children. Plasma samples were collected from 38 pediatric patients. Half of the patients received nonpulsatile flow and the other half underwent pulsatile flow during CPB. Plasma samples were collected at three time points: at baseline prior to incision (T1), 1 h after CPB (T2), and 24 h after CPB (T3). The study included 38 pediatric patients undergoing heart surgery (mean age 2.5 ± 2.1 years). Baseline apoE levels were low (<30 μg/mL) in 21 patients (55%). ApoE levels were significantly decreased at 1 h after CPB compared with baseline (22 ± 14 vs. 34 ± 18 μg/mL, P = 0.001). At 24 h after CPB, apoE levels were significantly increased compared with baseline (47 ± 25 vs. 34 ± 18 μg/mL, P = 0.002). Pulsatile mode was associated with lower apoE levels at 24 h after CPB compared with nonpulsatile mode (38 ± 14 vs. 57 ± 29 μg/mL, P = 0.018). ApoE levels correlated negatively with pump time (r = -0.525, P = 0.021) and cross-clamp time (r = -0.464, P = 0.045) at 24 h following CPB for the nonpulsatile group but not for the pulsatile group. In this cohort of young children with congenital heart disease, baseline apoE levels were low in the majority of patients prior to surgery. ApoE levels decreased further at 1 h after CPB, and then significantly increased by 24 h. The mode of perfusion and the duration of pump time and clamp time influence the apoE levels after CPB. An improved understanding of these mechanisms may translate into the development of new techniques to improve the clinical outcomes after pediatric CPB.

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“…Previous work indicated that caspase-3 targets Tau at Asp421 (Jarero-Basulto et al 2013). For a loading control mouse anti-Actin (Millipore, MAB1501R) (1:1000) was used.…”

Section: Methodsmentioning

confidence: 99%

Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging

et al. 2016

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Mouse models of neurodegenerative diseases such as Alzheimer’s disease (AD) are important for understanding how pathological signaling cascades change neural circuitry and in time interrupt cognitive function. Here, we introduce a non-genetic preclinical model for aging and show that it exhibits cleaved tau protein, active caspases and neurofibrillary tangles, hallmarks of AD, causing behavioral deficits measuring cognitive impairment. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans with potentially high impact on both new basic research into pathogenic mechanisms and new translational research efforts. Tau aggregation is a hallmark of tauopathies, including AD. Recent studies have indicated that cleavage of tau plays an important role in both tau aggregation and disease. In this study we use wild type mice as a model for normal aging and resulting age-related cognitive impairment. We provide evidence that aged mice have increased levels of activated caspases, which significantly correlates to increased levels of truncated tau and formation of neurofibrillary tangles. In addition, cognitive decline was significantly negatively associated with increased levels of caspase activity and tau truncated by caspase-3. Experimentally induced inhibition of caspases prevented this proteolytic cleavage of tau truncation and the associated formation of neurofibrillary tangles. Our study shows the strength of using a non-transgenic model to study structure, function and molecular mechanisms in aging and age related diseases of the brain.

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Proteolytic Cleavage of Polymeric Tau Protein by Caspase-3: Implications for Alzheimer Disease

Cited by 46 publications

References 94 publications

Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats

Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats

Apolipoprotein E Levels in Pediatric Patients Undergoing Cardiopulmonary Bypass

Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging

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