Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer's disease

Grynspan, Frida; Griffin, W. R.; Cataldo, Anne M.; Katayama, Sadao; Nixon, Ralph A.

doi:10.1016/s0006-8993(97)00384-3

Cited by 151 publications

(112 citation statements)

References 98 publications

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“…Furthermore, these experiments showed that calpain was able to cleave tau to generate a 17 kDa fragment as a final cleavage product. These data are in agreement with previous reports suggesting that calpain could play a role in AD (Grynspan et al, 1997;Tsuji et al, 1998;Veeranna et al, 2004). Thus, it has been shown that this Ca 2ϩ -dependent protease was abnormally activated in AD patients compared with age-matched controls (Saito et al, 1993).…”

Section: Discussionsupporting

confidence: 94%

The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration

Park¹,

Ferreira²

2005

J. Neurosci.

238

255

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Recently, we have shown that the microtubule-associated protein tau is essential for ␤-amyloid (A␤)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates A␤-induced neurite degeneration remain poorly understood. In the present study, we analyzed whether tau cleavage played a role in these events. Our results showed that pre-aggregated A␤ induced the generation of a 17 kDa tau fragment in cultured hippocampal neurons. The generation of this fragment was preceded by the activation of calpain-1. Conversely, inhibitors of this protease, but not of caspases, completely prevented tau proteolysis leading to the generation of the 17 kDa fragment and significantly reduced A␤-induced neuronal death. Furthermore, the expression of this fragment in cultured hippocampal neurons induced the formation of numerous varicosity-bearing tortuous processes, as well as the complete degeneration of some of those neurite processes. These results suggest that A␤-induced neurotoxicity may be mediated, at least in part, through the calpain-mediated generation of a toxic 17 kDa tau fragment. Collectively, these results provide insight into a novel mechanism by which tau could mediate A␤-induced neurotoxicity.

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Section: Discussionsupporting

confidence: 94%

The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration

Park¹,

Ferreira²

2005

J. Neurosci.

238

255

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“…Although the exact physiological role of calpains in the myocardium is not known, the ability of calpains to cleave cytoskeletal and myofilament proteins desmin, fodrin, filamin, C-protein, tropomyosin, troponin T, troponin I, nebulin, gelsolin, and vinculin in a variety of cell types, in vitro, suggest a regulatory role for calpains in remodeling of the myofibril (15)(16)(17). Calpain activity is increased in a wide variety of pathological conditions associated with calcium overload including Alzheimer's disease (18,19), cataracts (20), oxidative stress (21), and ischemia reperfusion injury (22). In post-ischemic myocardium, the proteolytic activity of calpain may be linked to degradation of sarcomeric proteins troponin I and desmin (17,23).…”

mentioning

confidence: 99%

Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes

Lim

Zuppinger

Guo

et al. 2004

Journal of Biological Chemistry

261

197

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Titin, the largest myofilament protein, serves as a template for sarcomere assembly and acts as a molecular spring to contribute to diastolic function. Titin is known to be extremely susceptible to calcium-dependent protease degradation in vitro. We hypothesized that titin degradation is an early event in doxorubicin-induced cardiac injury and that titin degradation occurs by activation of the calcium-dependent proteases, the calpains. Treatment of cultured adult rat cardiomyocytes with 1 or 3 mol/liter doxorubicin for 24 h resulted in degradation of titin in myocyte lysates, which was confirmed by a reduction in immunostaining of an antibody to the spring-like (PEVK) domain of titin at the I-band of the sarcomere. The elastic domain of titin appears to be most susceptible to proteolysis because co-immunostaining with an antibody to titin at the M-line was preserved, suggesting targeted proteolysis of the springlike domain of titin. Doxorubicin treatment for 1 h resulted in ϳ3-fold increase in calpain activity, which remained elevated at 48 h. Co-treatment with calpain inhibitors resulted in preservation of titin, reduction in myofibrillar disarray, and attenuation of cardiomyocyte necrosis but not apoptosis. Co-treatment with a caspase inhibitor did not prevent the degradation of titin, which precludes caspase-3 as an early mechanism of titin proteolysis. We conclude that calpain activation is an early event after doxorubicin treatment in cardiomyocytes and appears to target the degradation of titin. Proteolysis of the spring-like domain of titin may predispose cardiomyocytes to diastolic dysfunction, myofilament instability, and cell death by necrosis.

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“…Deletion of the last 300-400 residues of ␣ 1 1.2 increases channel activity when expressed in Xenopus oocytes (29); therefore, calpain-mediated cleavage may permanently elevate Ca v 1.2 activity in vivo. Because calpain has been implicated in the etiology of Alzheimer's disease (30,31), we initially investigated whether the ratio of long-form ␣ 1 1.2 to short-form ␣ 1 1.2 is changed in old rats. The amount of long-form ␣ 1 1.2 was unaltered, and short-form ␣ 1 1.2 was slightly decreased in old rats, which suggests that calpain-mediated processing is not responsible for the increase in L-type channel activity during aging.…”

mentioning

confidence: 99%

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Davare

Hell

2003

Proc. Natl. Acad. Sci. U.S.A.

110

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An increase in Ca 2؉ influx through L-type Ca 2؉ channels is thought to contribute to neuronal dysfunctions that underlie senile symptoms and Alzheimer's disease. The molecular basis of the agedependent up-regulation in neuronal L-type Ca 2؉ channel activity is largely unknown. We show that phosphorylation of the L-type channel Ca v1.2 by cAMP-dependent protein kinase is increased >2-fold in the hippocampus of aged rats. The hippocampus is critical for learning and is one of the first brain regions to be affected in Alzheimer's disease. Phosphorylation of Ca v1.2 by cAMP-dependent protein kinase strongly enhances its activity. Therefore, increased Ca v1.2 phosphorylation may account for a substantial portion of the age-related rise in neuronal Ca 2؉ influx and its neuropathological consequences. C a 2ϩ regulates a variety of signaling pathways (1-3). Acute uncontrolled Ca 2ϩ influx can cause neuronal death by overstimulation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (4, 5). Chronic elevation of Ca 2ϩ influx has been implicated in age-associated neuronal loss and Alzheimer's disease (6, 7). The age-related learning impairment in rabbits is reversed by the specific L-type Ca 2ϩ channel blocker nimodipine (8). These observations indicate that elevation of L-type channel activity causes neuronal dysfunction during aging. Ca 2ϩ influx through L-type channels is up-regulated Ͼ2-fold in hippocampal neurons of old versus adult rats (9). The hippocampus is crucial for learning and memory; however, the molecular basis for the increase in L-type channel activity during aging is not well defined, except for an Ϸ20% increase in Ca v 1.3 protein (10, 11). We now show that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of the L-type channel Ca v 1.2 increases Ͼ2-fold during aging and that it may underlie a substantial portion of the age-related increase in L-type channel activity.PKA increases L-type channel activity in neurons (13-16) and in the heart, where PKA-dependent stimulation of the cardiac L-type channel is crucial for the up-regulation of the heartbeat after adrenergic stimulation (17, 18 (19), and the auxiliary subunits ␣ 2 -␦, -␤, and -␥ (22). Only ␣ 1 1.2, and none of the auxiliary subunits, is required for the PKA-mediated increase in channel activity (23). ␣ 1 1.2 is phosphorylated in intact hippocampal neurons by PKA (24). The main phosphorylation site on ␣ 1 1.2 is serine 1928 (25, 26), which is important for the up-regulation of the channel activity by PKA (27). This site is close to the C terminus of ␣ 1 1.2, is present only in the full-length form of ␣ 1 1.2 (21), and is removed by the Ca 2ϩ -activated protease calpain after Ca 2ϩ influx through NMDA receptors (28). Calpain cleaves ␣ 1 1.2 Ϸ300 residues upstream of the C terminus in vitro (28). Deletion of the last 300-400 residues of ␣ 1 1.2 increases channel activity when expressed in Xenopus oocytes (29); therefore, calpain-mediated cleavage may permanently elevate Ca v 1.2 activity in vivo. Because calpain has been impli...

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Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer's disease

Cited by 151 publications

References 98 publications

The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration

The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration

Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

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Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer's disease

Cited by 151 publications

References 98 publications

The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration

The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration

Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes

Increased phosphorylation of the neuronal L-type Ca 2+ channel Ca v 1.2 during aging

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Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging