Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease

J. Steven Jacobsen, Chi Cheng Wu, Jeffrey M. Redwine, Thomas A. Comery, Robert Arias, Mark Bowlby, Robert Martone, John Morrison, Menelas M. Pangalos, Peter H. Reinhart, Floyd E. Bloom

Research output: Contribution to journalArticle

521 Scopus citations

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 languageEnglish (US)
Pages (from-to)5161-5166
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number13
DOIs
StatePublished - Mar 28 2006
Externally publishedYes

Keywords

  • β-amyloid
  • Cognition

ASJC Scopus subject areas

  • General

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    Jacobsen, J. S., Wu, C. C., Redwine, J. M., Comery, T. A., Arias, R., Bowlby, M., Martone, R., Morrison, J., Pangalos, M. M., Reinhart, P. H., & Bloom, F. E. (2006). Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 103(13), 5161-5166. https://doi.org/10.1073/pnas.0600948103