Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer's Disease

Alzheimer's type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1-42 (A beta), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low A beta in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by A beta and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with A beta and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, A beta and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low A beta and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders

DHEAS increases levels of GluR2/3 and GluR2, AMPA receptor subunits, in C57BL/6 mice hippocampus

ABSTRACT: Dehydroepiandrosterone sulfate (DHEA-S) is a neurosteroid that has effects such as neuromodulator of synaptic transmission and neuroprotection. The specific signaling pathways for these effects are not elucidated yet. Given that, some neurosteroids act through the activation of ionotropic glutamate receptors, therefore the effect of DHEA-S on the subunits GluR2 and GluR3 of the AMPA receptor was evaluated. Either DHEA-S or a control substance was administered to C57/BL6 mice. Subunit expression of the AMPA receptor was analyzed by Western blotting. Results show that long-term DHEA-S administration to C57/BL6 mice, increases the protein levels of the subunits GluR2 and GluR2/3 of the AMPA receptors located in the hippocampus. Due to the role of AMPA receptor, specifically GluR2 subunit in the regulation of intracellular calcium levels, cellular apoptosis, and synaptic plasticity, the study of neurosteroids as a therapeutic strategy in neurodegenerative diseases and cerebrovascular events is very relevant.RESUMEN: El DHEAS es un neuroesteroide con efecto neuromodulador de la transmisión sináptica y en la neuroprotección, sin embargo las vías moleculares a través de las cuales se inducen estos cambios no están completamente claras. Como varios de los neuroesteroides actúan a través de los recetores ionotrópicos de glutamato, se evaluó el efecto del DHEAS en las subunidades GluR2 y GluR3 del receptor AMPA para esclarecer sus efectos. Con este fin se administró DHEAS o una sustancia control durante 7 días a ratones C57/BL6. La expresión de las subunidades se evaluó por Western blotting. Los resultados presentados muestran que la administración prolongada de 40mg/kg/día de DHEAS a ratones C57/BL6 produce un incremento en los niveles de proteína de las subunidades GluR2/3 y GluR2 del receptor AMPA en el hipocampo. Dado el papel específico que juega la subunidad GluR2 del receptor AMPA en el control de la entrada de calcio durante los procesos de muerte celular y de plasticidad sináptica, este hallazgo contribuye al estudio de los neuroesteroides como una estrategia terapéutica relevante en enfermedades neurodegenerativas y eventos cerebrovasculares

Ceramida como primer mensajero en eventos de muerte celular

Actaulmente esta claro que el papel fundamental que cumplen los lípidos en toda clase de procesos celulares y concretamente en el funcionamientodel sistema nervioso

DHEAS increases levels of GluR2/3 and GluR2, AMPA receptor subunits, in C57BL/6 mice hippocampus El DHEAS incrementa la expresión de GluR2/3 y GLUR2 del receptor AMPA en el hipocampo de ratones C57/BL6

<p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Dehydroepiandrosterone sulfate (DHEA-S) is a neurosteroid that has effects such as neuromodulator of synaptic transmission and neuroprotection. The specific signaling pathways for these effects are not elucidated yet. Given that, some neurosteroids act through the activation of ionotropic glutamate receptors, therefore the effect of DHEA-S on the subunits GluR2 <span style="mso-spacerun: yes;"> </span>and GluR3 of the AMPA receptor was evaluated. <span style="mso-spacerun: yes;"> </span>Either DHEA-S or a control substance was administered to C57/BL6 mice. Subunit expression of the AMPA receptor was analyzed by Western blotting.</span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US"> </span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US"> </span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Results show that long-term DHEA-S administration to C57/BL6 mice, increases the protein levels of the subunits GluR2 and GluR2/3 of the AMPA receptors located in the hippocampus.</span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US"> </span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Due to the role of AMPA receptor, specifically <span style="mso-spacerun: yes;"> </span>GluR2 <span style="mso-spacerun: yes;"> </span>subunit <span style="mso-spacerun: yes;"> </span>in <span style="mso-spacerun: yes;"> </span>the <span style="mso-spacerun: yes;"> </span>regulation of intracellular <span style="mso-spacerun: yes;"> </span>calcium <span style="mso-spacerun: yes;"> </span>levels, cellular <span style="mso-spacerun: yes;"> </span>apoptosis, and <span style="mso-spacerun: yes;"> </span>synaptic <span style="mso-spacerun: yes;"> </span>plasticity, the <span style="mso-spacerun: yes;"> </span>study <span style="mso-spacerun: yes;"> </span>of </span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">neurosteroids as a therapeutic strategy in neurodegenerative diseases and cerebrovascular events is very relevant.</span></p> <p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ">El DHEAS es un neuroesteroide con efecto neuromodulador de la transmisión sináptica y en la neuroprotección, sin embargo las vías moleculares a través de las cuales se inducen estos cambios no están completamente claras. Como varios de los neuroesteroides actúan a través de los recetores ionotrópicos de glutamato, se evaluó el efecto del DHEAS en las subunidades GluR2 y GluR3 del receptor AMPA para esclarecer sus efectos. Con este fin se administró DHEAS o una sustancia control durante 7 días a ratones C57/BL6. La expresión de las subunidades se evaluó por Western blotting.</span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: "> </span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ">Los resultados presentados muestran que la administración prolongada de 40mg/kg/día de DHEAS a ratones C57/BL6 produce un incremento en los niveles de proteína de las subunidades GluR2/3 y GluR2 del receptor AMPA en el hipocampo.</span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: "> </span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: ">Dado el papel específico que juega la subunidad GluR2 del receptor AMPA en el control de la entrada de calcio durante los procesos de muerte celular y de plasticidad sináptica, este hallazgo contribuye al estudio de los neuroesteroides como una estrategia terapéutica relevante en enfermedades neurodegenerativas y eventos cerebrovasculares.</span></p><p class="MsoNormal" style="text-align: justify; line-height: normal; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="font-family: "> </span></p><p> </p&gt