Abstract
Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (aSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric aSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of aSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human aSyn in an AD mouse model, we artificially enhanced aSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble aSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric aSyn but not monomeric aSyn was causing a lowering in synapsin-I/II protein abundance. For a particular aSyn oligomer, these changes were either dependent or independent on endogenous aSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by aSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous aSyn oligomers can impair memory by selectively lowering synapsin expression.
| Original language | English (US) |
|---|---|
| Pages (from-to) | E4648-E4657 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 114 |
| Issue number | 23 |
| DOIs | |
| State | Published - Jun 6 2017 |
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Keywords
- Alzheimer's disease
- Memory
- Oligomer
- Synapsins
- α-synuclein
ASJC Scopus subject areas
- General
Cite this
Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits. / Larson, Megan E.; Greimel, Susan J.; Amar, Fatou; LaCroix, Michael; Boyle, Gabriel; Sherman, Mathew A.; Schley, Hallie; Miel, Camille; Schneider, Julie A.; Kayed, Rakez; Benfenati, Fabio; Lee, Michael K.; Bennett, David A.; Lesné, Sylvain E.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 23, 06.06.2017, p. E4648-E4657.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits
AU - Larson, Megan E.
AU - Greimel, Susan J.
AU - Amar, Fatou
AU - LaCroix, Michael
AU - Boyle, Gabriel
AU - Sherman, Mathew A.
AU - Schley, Hallie
AU - Miel, Camille
AU - Schneider, Julie A.
AU - Kayed, Rakez
AU - Benfenati, Fabio
AU - Lee, Michael K.
AU - Bennett, David A.
AU - Lesné, Sylvain E.
PY - 2017/6/6
Y1 - 2017/6/6
N2 - Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (aSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric aSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of aSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human aSyn in an AD mouse model, we artificially enhanced aSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble aSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric aSyn but not monomeric aSyn was causing a lowering in synapsin-I/II protein abundance. For a particular aSyn oligomer, these changes were either dependent or independent on endogenous aSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by aSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous aSyn oligomers can impair memory by selectively lowering synapsin expression.
AB - Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (aSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric aSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of aSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human aSyn in an AD mouse model, we artificially enhanced aSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble aSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric aSyn but not monomeric aSyn was causing a lowering in synapsin-I/II protein abundance. For a particular aSyn oligomer, these changes were either dependent or independent on endogenous aSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by aSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous aSyn oligomers can impair memory by selectively lowering synapsin expression.
KW - Alzheimer's disease
KW - Memory
KW - Oligomer
KW - Synapsins
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85020263417&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020263417&partnerID=8YFLogxK
U2 - 10.1073/pnas.1704698114
DO - 10.1073/pnas.1704698114
M3 - Article
VL - 114
SP - E4648-E4657
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 23
ER -