Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of β-amyloid (Aβ)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Aβ42 Aβ40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5161-5166 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 103 |
| Issue number | 13 |
| DOIs | |
| State | Published - Mar 28 2006 |
| Externally published | Yes |
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Keywords
- β-amyloid
- Cognition
ASJC Scopus subject areas
- General
Cite this
Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. / Jacobsen, J. Steven; Wu, Chi Cheng; Redwine, Jeffrey M.; Comery, Thomas A.; Arias, Robert; Bowlby, Mark; Martone, Robert; Morrison, John; Pangalos, Menelas M.; Reinhart, Peter H.; Bloom, Floyd E.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 13, 28.03.2006, p. 5161-5166.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease
AU - Jacobsen, J. Steven
AU - Wu, Chi Cheng
AU - Redwine, Jeffrey M.
AU - Comery, Thomas A.
AU - Arias, Robert
AU - Bowlby, Mark
AU - Martone, Robert
AU - Morrison, John
AU - Pangalos, Menelas M.
AU - Reinhart, Peter H.
AU - Bloom, Floyd E.
PY - 2006/3/28
Y1 - 2006/3/28
N2 - Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of β-amyloid (Aβ)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Aβ42 Aβ40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.
AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of β-amyloid (Aβ)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Aβ42 Aβ40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.
KW - β-amyloid
KW - Cognition
UR - http://www.scopus.com/inward/record.url?scp=33645520634&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645520634&partnerID=8YFLogxK
U2 - 10.1073/pnas.0600948103
DO - 10.1073/pnas.0600948103
M3 - Article
C2 - 16549764
AN - SCOPUS:33645520634
VL - 103
SP - 5161
EP - 5166
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 - 13
ER -