The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease
Based on previous evidence that the non-steroidal estrogen receptor modulator STX mitigates the effects of neurotoxic Amyloid-β (Aβ) in vitro, we have evaluated its neuroprotective benefits in a mouse model of Alzheimer's disease. Cohorts of 5XFAD mice, which begin to accumulate cerebral Aβ at...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996122002807 |
| _version_ | 1811257383961231360 |
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| author | Joseph F. Quinn Martin J. Kelly Christopher J. Harris Wyatt Hack Nora E. Gray Veronika Kulik Zoe Bostick Barbara H. Brumbach Philip F. Copenhaver |
| author_facet | Joseph F. Quinn Martin J. Kelly Christopher J. Harris Wyatt Hack Nora E. Gray Veronika Kulik Zoe Bostick Barbara H. Brumbach Philip F. Copenhaver |
| author_sort | Joseph F. Quinn |
| collection | DOAJ |
| description | Based on previous evidence that the non-steroidal estrogen receptor modulator STX mitigates the effects of neurotoxic Amyloid-β (Aβ) in vitro, we have evaluated its neuroprotective benefits in a mouse model of Alzheimer's disease. Cohorts of 5XFAD mice, which begin to accumulate cerebral Aβ at two months of age, were treated with orally-administered STX starting at 6 months of age for two months. After behavioral testing to evaluate cognitive function, biochemical and immunohistochemical assays were used to analyze key markers of mitochondrial function and synaptic integrity. Oral STX treatment attenuated Aβ-associated mitochondrial toxicity and synaptic toxicity in the brain, as previously documented in cultured neurons. STX also moderately improved spatial memory in 5XFAD mice. In addition, STX reduced markers for reactive astrocytosis and microgliosis surrounding amyloid plaques, and also unexpectedly reduced overall levels of cerebral Aβ in the brain. The neuroprotective effects of STX were more robust in females than in males. These results suggest that STX may have therapeutic potential in Alzheimer's Disease. |
| first_indexed | 2024-04-12T17:55:38Z |
| format | Article |
| id | doaj.art-782f7a69b4644a658b5e92462ffc06b9 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-12T17:55:38Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-782f7a69b4644a658b5e92462ffc06b92022-12-22T03:22:21ZengElsevierNeurobiology of Disease1095-953X2022-11-01174105888The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's diseaseJoseph F. Quinn0Martin J. Kelly1Christopher J. Harris2Wyatt Hack3Nora E. Gray4Veronika Kulik5Zoe Bostick6Barbara H. Brumbach7Philip F. Copenhaver8Department of Neurology, Oregon Health and Science University, Portland, OR, United States of America; Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, United States of America; Corresponding author at: Department of Neurology, Oregon Health and Science University, Portland, OR, United States of America.Department of Chemical Physiology and Biochemistry, OHSU, Portland, OR, United States of AmericaDepartment of Neurology, Oregon Health and Science University, Portland, OR, United States of AmericaDepartment of Neurology, Oregon Health and Science University, Portland, OR, United States of AmericaDepartment of Neurology, Oregon Health and Science University, Portland, OR, United States of AmericaDepartment of Neurology, Oregon Health and Science University, Portland, OR, United States of AmericaDepartment of Cell, Developmental and Cancer Biology, OHSU, Portland, OR, United States of AmericaBiostatistics and Design Program, OHSU-PSU School of Public Health, Portland, OR, United States of AmericaDepartment of Cell, Developmental and Cancer Biology, OHSU, Portland, OR, United States of AmericaBased on previous evidence that the non-steroidal estrogen receptor modulator STX mitigates the effects of neurotoxic Amyloid-β (Aβ) in vitro, we have evaluated its neuroprotective benefits in a mouse model of Alzheimer's disease. Cohorts of 5XFAD mice, which begin to accumulate cerebral Aβ at two months of age, were treated with orally-administered STX starting at 6 months of age for two months. After behavioral testing to evaluate cognitive function, biochemical and immunohistochemical assays were used to analyze key markers of mitochondrial function and synaptic integrity. Oral STX treatment attenuated Aβ-associated mitochondrial toxicity and synaptic toxicity in the brain, as previously documented in cultured neurons. STX also moderately improved spatial memory in 5XFAD mice. In addition, STX reduced markers for reactive astrocytosis and microgliosis surrounding amyloid plaques, and also unexpectedly reduced overall levels of cerebral Aβ in the brain. The neuroprotective effects of STX were more robust in females than in males. These results suggest that STX may have therapeutic potential in Alzheimer's Disease.http://www.sciencedirect.com/science/article/pii/S0969996122002807AmyloidAlzheimer'sEstrogenMitochondriaReactive astrocytosisMicrogliosis |
| spellingShingle | Joseph F. Quinn Martin J. Kelly Christopher J. Harris Wyatt Hack Nora E. Gray Veronika Kulik Zoe Bostick Barbara H. Brumbach Philip F. Copenhaver The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease Neurobiology of Disease Amyloid Alzheimer's Estrogen Mitochondria Reactive astrocytosis Microgliosis |
| title | The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease |
| title_full | The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease |
| title_fullStr | The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease |
| title_full_unstemmed | The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease |
| title_short | The novel estrogen receptor modulator STX attenuates Amyloid-β neurotoxicity in the 5XFAD mouse model of Alzheimer's disease |
| title_sort | novel estrogen receptor modulator stx attenuates amyloid β neurotoxicity in the 5xfad mouse model of alzheimer s disease |
| topic | Amyloid Alzheimer's Estrogen Mitochondria Reactive astrocytosis Microgliosis |
| url | http://www.sciencedirect.com/science/article/pii/S0969996122002807 |
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