Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia
Abstract Background Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated an...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-10-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-021-02281-1 |
| _version_ | 1818724702687854592 |
|---|---|
| author | Christina Hoyer-Kimura John P. Konhilas Heidi M. Mansour Robin Polt Kristian P. Doyle Dean Billheimer Meredith Hay |
| author_facet | Christina Hoyer-Kimura John P. Konhilas Heidi M. Mansour Robin Polt Kristian P. Doyle Dean Billheimer Meredith Hay |
| author_sort | Christina Hoyer-Kimura |
| collection | DOAJ |
| description | Abstract Background Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1–7 (Ang-(1–7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1–7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model. Methods VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1–7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05. Results Treatment with Ang-(1–7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain. Conclusions These data show that treatment with Ang-(1–7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement. |
| first_indexed | 2024-12-17T21:30:37Z |
| format | Article |
| id | doaj.art-1f581aace31e48588560b1ea25934274 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-17T21:30:37Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-1f581aace31e48588560b1ea259342742022-12-21T21:31:53ZengBMCJournal of Neuroinflammation1742-20942021-10-0118111710.1186/s12974-021-02281-1Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementiaChristina Hoyer-Kimura0John P. Konhilas1Heidi M. Mansour2Robin Polt3Kristian P. Doyle4Dean Billheimer5Meredith Hay6Department of Physiology, The University of ArizonaDepartment of Physiology, The University of ArizonaDepartment of Pharmacy, Skaggs Pharmaceutical Sciences Center, The University of ArizonaDepartment of Chemistry and Biochemistry, The University of ArizonaDepartment of Immunobiology, The University of ArizonaDepartment of Epidemiology and Biostatistics, The University of ArizonaDepartment of Physiology, The University of ArizonaAbstract Background Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1–7 (Ang-(1–7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1–7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model. Methods VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1–7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05. Results Treatment with Ang-(1–7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain. Conclusions These data show that treatment with Ang-(1–7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.https://doi.org/10.1186/s12974-021-02281-1Neurofilament light (NfL)BiomarkerVascular contributions to cognitive impairment and dementiaInflammationPNA5Angiotensin-(1–7) |
| spellingShingle | Christina Hoyer-Kimura John P. Konhilas Heidi M. Mansour Robin Polt Kristian P. Doyle Dean Billheimer Meredith Hay Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia Journal of Neuroinflammation Neurofilament light (NfL) Biomarker Vascular contributions to cognitive impairment and dementia Inflammation PNA5 Angiotensin-(1–7) |
| title | Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia |
| title_full | Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia |
| title_fullStr | Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia |
| title_full_unstemmed | Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia |
| title_short | Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia |
| title_sort | neurofilament light a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia |
| topic | Neurofilament light (NfL) Biomarker Vascular contributions to cognitive impairment and dementia Inflammation PNA5 Angiotensin-(1–7) |
| url | https://doi.org/10.1186/s12974-021-02281-1 |
| work_keys_str_mv | AT christinahoyerkimura neurofilamentlightapossibleprognosticbiomarkerfortreatmentofvascularcontributionstocognitiveimpairmentanddementia AT johnpkonhilas neurofilamentlightapossibleprognosticbiomarkerfortreatmentofvascularcontributionstocognitiveimpairmentanddementia AT heidimmansour neurofilamentlightapossibleprognosticbiomarkerfortreatmentofvascularcontributionstocognitiveimpairmentanddementia AT robinpolt neurofilamentlightapossibleprognosticbiomarkerfortreatmentofvascularcontributionstocognitiveimpairmentanddementia AT kristianpdoyle neurofilamentlightapossibleprognosticbiomarkerfortreatmentofvascularcontributionstocognitiveimpairmentanddementia AT deanbillheimer neurofilamentlightapossibleprognosticbiomarkerfortreatmentofvascularcontributionstocognitiveimpairmentanddementia AT meredithhay neurofilamentlightapossibleprognosticbiomarkerfortreatmentofvascularcontributionstocognitiveimpairmentanddementia |