β‐Amyloid increases somatostatin expression in cultured cortical neurons

Geci, Catherine; How, Jonathan P.; Alturaihi, Haydar; Kumar, Ujendra

doi:10.1111/j.1471-4159.2006.04415.x

Cited by 26 publications

(25 citation statements)

References 36 publications

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“…[23][24][25] However, it is still unknown about the exact molecular mechanisms of Ab-mediated neuronal apoptosis. Thus, our study was first started from the two aspects of cellular viability and survival rate.…”

Section: Discussionmentioning

confidence: 99%

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

Zeng

Zong

Zhang

et al. 2015

Rejuvenation Research

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Our previous study suggests that ginger root extract can reverse behavioral dysfunction and prevent Alzheimer's disease (AD)-like symptoms induced by the amyloid-b protein (Ab) in a rat model. 6-Gingerol is the major gingerol in ginger rhizomes, but its effect on the treatment of AD remains unclear. In this study, we aimed to determine if 6-gingerol had a protective effect on Ab 1-42 -induced damage and apoptotic death in rat pheochromocytoma cells (PC12 cells) and to investigate the underlying mechanisms by which 6-gingerol may exert its neuroprotective effects. Our results indicated that pre-treatment with 6-gingerol significantly increased cell viability and reduced cell apoptosis in Ab 1-42 -treated cells. Moreover, 6-gingerol pretreatment markedly reduced the level of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), the production of nitric oxide (NO), and the leakage of lactate dehydrogenase (LDH) and increased superoxide dismutase (SOD) activity compared with the Ab 1-42 treatment group. In addition, 6-gingerol pretreatment also significantly enhanced the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3b (p-GSK-3b). Overall, these results indicate that 6-gingerol exhibited protective effects on apoptosis induced by Ab 1-42 in cultured PC12 cells by reducing oxidative stress and inflammatory responses, suppressing the activation of GSK-3b and enhancing the activation of Akt, thereby exerting neuroprotective effects. Therefore, 6-gingerol may be useful in the prevention and/or treatment of AD.

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Section: Discussionmentioning

confidence: 99%

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

Zeng

Zong

Zhang

et al. 2015

Rejuvenation Research

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show abstract

“…48 Moreover, in cell culture models, A␤ [25][26][27][28][29][30][31][32][33][34][35] was reported to induce apoptosis at lower concentrations (5 and 10 mol/L) 5 and necrosis at higher concentrations (20 and 40 mol/L). 49 Oxidative stress, apoptosis, and morphological damage induced by amyloid peptides suggest deficits in endogenous neuroprotective mechanisms. Among these, BDNF is known to protect neurons against various types of brain insult.…”

Section: Discussionmentioning

confidence: 99%

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Zussy

Brureau

Delair

et al. 2011

The American Journal of Pathology

121

129

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Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid ␤ protein (A␤) formed by pathological processing of the A␤ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated A␤ fragment 25-35 (A␤ 25-35 ) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled A␤ 25-35 peptide was used as negative control. The aggregated forms of A␤ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of A␤ 25-35 decreased body weight, induced short-and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, A␤ 25-35 , the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. Alzheimer's disease (AD) is a chronic neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss in brain areas responsible for learning and memory impairments. 1 The major component of senile plaques is an amyloid ␤ protein (A␤) derived from amyloid precursor protein (APP). Genetic, cell biological, and postmortem studies on AD brain, together with A␤ neurotoxicity findings, gave rise to the amyloid cascade hypothesis to explain A␤-associated neurodegenerative processes. 2 In normal healthy individuals, A␤ peptides are present only in small quantities, as soluble monomers that circulate in cerebrospinal fluid and blood. In AD patients, A␤ peptides, which vary in length from 40 to 43 amino acids, accumulate as insoluble fibrillar deposits. 3 When cultured rat hippocampal neurons are exposed to aggregated A␤ peptides, their neurites adopt a dystrophic appearance and become comparable to those observed surrounding and infiltrating senile plaques. This observation suggested that A␤ is responsible for the neuritic abnormalities in AD pathology. 4 Structure-activity studies revealed that peptides containing the highly hydrophobic 25-35 region formed stable aggregates and mediated neuronal death by necrosis or apoptosis. 5,6,7 The truncated A␤ 25-35 fragment includes extracellular and intramembrane residues that have been reported to represent an active region of A␤. 8

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“…16 Recently, it has been shown that somatostatin regulates β-amyloid metabolism by increasing the enzymatic activity of neprilysin (which is the most important enzyme responsible for the hydrolysis of β-amyloid together with IDE) in primary cortical neurons; a modification of neprilysin localization induced by somatostatin has also been observed. 19,23,24 Altogether, the available data suggest a possible role of both IDE and somatostatin in the pathogenesis of AD. Therefore, a characterization of somatostatin-IDE interaction and its functional effect on IDE activity should cast some light on the molecular interrelationships at the origin of the pathophysiological events of AD.…”

Section: Introductionmentioning

confidence: 94%

Somatostatin: A Novel Substrate and a Modulator of Insulin-Degrading Enzyme Activity

Ciaccio

Tundo

Grasso

et al. 2009

Journal of Molecular Biology

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Insulin-degrading enzyme (IDE) is an interesting pharmacological target for Alzheimer's disease (AD), since it hydrolyzes β-amyloid, producing nonneurotoxic fragments. It has also been shown that the somatostatin level reduction is a pathological feature of AD and that it regulates the neprilysin activity toward β-amyloid.In this work, we report for the first time that IDE is able to hydrolyze somatostatin [k cat (s − 1 ) = 0.38 (±0.05); K m (M) = 7.5 (±0.9)× 10 − 6 ] at the Phe6-Phe7 amino acid bond. On the other hand, somatostatin modulates IDE activity, enhancing the enzymatic cleavage of a novel fluorogenic β-amyloid through a decrease of the K m toward this substrate, which corresponds to the 10-25 amino acid sequence of the Aβ(1-40). Circular dichroism spectroscopy and surface plasmon resonance imaging experiments show that somatostatin binding to IDE brings about a concentration-dependent structural change of the secondary and tertiary structure(s) of the enzyme, revealing two possible binding sites. The higher affinity binding site disappears upon inactivation of IDE by ethylenediaminetetraacetic acid, which chelates the catalytic Zn 2+ ion. As a whole, these features suggest that the modulatory effect is due to an allosteric mechanism: somatostatin binding to the active site of one IDE subunit (where somatostatin is cleaved) induces an enhancement of IDE proteolytic activity toward fluorogenic β-amyloid by another subunit. Therefore, this investigation on IDE-somatostatin interaction contributes to a more exhaustive knowledge about the functional and structural aspects of IDE and its pathophysiological implications in the amyloid deposition and somatostatin homeostasis in the brain.

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β‐Amyloid increases somatostatin expression in cultured cortical neurons

Cited by 26 publications

References 36 publications

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Somatostatin: A Novel Substrate and a Modulator of Insulin-Degrading Enzyme Activity

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