TY - JOUR

T1 - Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties

AU - Tikhonova, Maria A.

AU - Amstislavskaya, Tamara G.

AU - Belichenko, Victor M.

AU - Fedoseeva, Larisa A.

AU - Kovalenko, Sergey P.

AU - Pisareva, Ekaterina E.

AU - Avdeeva, Alla S.

AU - Kolosova, Nataliya G.

AU - Belyaev, Nikolai D.

AU - Aftanas, Lyubomir I.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - Background: The dominant hypothesis about the pathogenesis of Alzheimer's disease (AD) is the "amyloid cascade" concept and modulating the expression of proteins involved in the metabolism of amyloid-beta (Aβ) is proposed as an effective strategy for the prevention and therapy of AD. Recently, we found that an antibiotic ceftriaxone (CEF), which possesses neuroprotective activity, reduced cognitive deficits and neurodegenerative changes in OXYS rats, a model of sporadic AD. The molecular mechanisms of this effect are not completely clear, we suggested that the drug might serve as the regulator of the expression of the genes involved in the metabolism of Aβ and the pathogenesis of AD. The study was aimed to determine the effects of CEF on mRNA levels of Bace1 (encoding β-secretase BACE1 involved in Aβ production), Mme, Ide, Ece1, Ace2 (encoding enzymes involved in Aβ degradation), Epo (encoding erythropoietin related to endothelial function and clearance of Aβ across the blood brain barrier) in the frontal cortex, hippocampus, striatum, hypothalamus, and amygdala of OXYS and Wistar (control strain) male rats. Starting from the age of 14 weeks, animals received CEF (100 mg/kg/day, i.p., 36 days) or saline. mRNA levels were evaluated with RT-qPCR method. Biochemical parameters of plasma were measured for control of system effects of the treatment. Results: To better understand strain variations studied here, we compared the gene expression between untreated OXYS and Wistar rats. This comparison showed a significant decrease in mRNA levels of Ace2 in the frontal cortex and hypothalamus, and of Actb in the amygdala of untreated OXYS rats. Analysis of potential effects of CEF revealed its novel targets. In the compound-treated OXYS cohort, CEF diminished mRNA levels of Bace1 and Ace2 in the hypothalamus, and Aktb in the frontal cortex. Furthermore, CEF augmented Mme, Ide, and Epo mRNA levels in the amygdala as well as the levels of Ece1 and Aktb in the striatum. Finally, CEF also attenuated the activity of ALT and AST in plasma of OXYS rats. Conclusion: Those findings disclosed novel targets for CEF action that might be involved into neuroprotective mechanisms at early, pre-plaque stages of AD-like pathology development.

AB - Background: The dominant hypothesis about the pathogenesis of Alzheimer's disease (AD) is the "amyloid cascade" concept and modulating the expression of proteins involved in the metabolism of amyloid-beta (Aβ) is proposed as an effective strategy for the prevention and therapy of AD. Recently, we found that an antibiotic ceftriaxone (CEF), which possesses neuroprotective activity, reduced cognitive deficits and neurodegenerative changes in OXYS rats, a model of sporadic AD. The molecular mechanisms of this effect are not completely clear, we suggested that the drug might serve as the regulator of the expression of the genes involved in the metabolism of Aβ and the pathogenesis of AD. The study was aimed to determine the effects of CEF on mRNA levels of Bace1 (encoding β-secretase BACE1 involved in Aβ production), Mme, Ide, Ece1, Ace2 (encoding enzymes involved in Aβ degradation), Epo (encoding erythropoietin related to endothelial function and clearance of Aβ across the blood brain barrier) in the frontal cortex, hippocampus, striatum, hypothalamus, and amygdala of OXYS and Wistar (control strain) male rats. Starting from the age of 14 weeks, animals received CEF (100 mg/kg/day, i.p., 36 days) or saline. mRNA levels were evaluated with RT-qPCR method. Biochemical parameters of plasma were measured for control of system effects of the treatment. Results: To better understand strain variations studied here, we compared the gene expression between untreated OXYS and Wistar rats. This comparison showed a significant decrease in mRNA levels of Ace2 in the frontal cortex and hypothalamus, and of Actb in the amygdala of untreated OXYS rats. Analysis of potential effects of CEF revealed its novel targets. In the compound-treated OXYS cohort, CEF diminished mRNA levels of Bace1 and Ace2 in the hypothalamus, and Aktb in the frontal cortex. Furthermore, CEF augmented Mme, Ide, and Epo mRNA levels in the amygdala as well as the levels of Ece1 and Aktb in the striatum. Finally, CEF also attenuated the activity of ALT and AST in plasma of OXYS rats. Conclusion: Those findings disclosed novel targets for CEF action that might be involved into neuroprotective mechanisms at early, pre-plaque stages of AD-like pathology development.

KW - Alzheimer's disease

KW - Amyloid metabolism

KW - Ceftriaxone

KW - Gene expression

KW - MRNA

KW - Neuroprotection

KW - Rats

KW - Gene Expression/drug effects

KW - Neuroprotective Agents/administration & dosage

KW - Rats, Wistar

KW - Male

KW - RNA, Messenger/metabolism

KW - Brain/drug effects

KW - Animals

KW - Ceftriaxone/administration & dosage

KW - Alzheimer Disease/drug therapy

KW - Amyloid beta-Peptides/metabolism

KW - Disease Models, Animal

KW - ALZHEIMERS-DISEASE

KW - ACCELERATED OXYS RATS

KW - DISEASE-LIKE PATHOLOGY

KW - mRNA

KW - ANGIOTENSIN-CONVERTING ENZYME

KW - DEFICITS

KW - ERYTHROPOIETIN

KW - APP INTRACELLULAR DOMAIN

KW - MODEL

KW - COGNITIVE DECLINE

KW - HISTOCHROME

UR - http://www.scopus.com/inward/record.url?scp=85045537930&partnerID=8YFLogxK

U2 - 10.1186/s12868-018-0412-5

DO - 10.1186/s12868-018-0412-5

M3 - Article

C2 - 29745864

AN - SCOPUS:85045537930

VL - 19

SP - 13

JO - BMC Neuroscience

JF - BMC Neuroscience

SN - 1471-2202

IS - Suppl 1

M1 - 13

ER -