Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease.
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 beta-amyloid (Abeta)-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 Abeta42/Abeta40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until approximately 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.
Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA. jacobss@wyeth.com
J Steven
JS
Jacobsen
Chi-Cheng
CC
Wu
Jeffrey M
JM
Redwine
Thomas A
TA
Comery
Robert
R
Arias
Mark
M
Bowlby
Robert
R
Martone
John H
JH
Morrison
Menelas N
MN
Pangalos
Peter H
PH
Reinhart
Floyd E
FE
Bloom
D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005239:Fear; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D013131:Spine / Q000473:pathology; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016708:Synaptophysin