Presentation Abstract

Program#/Poster#: 526.10/G33
Title: APP/Aβ expression in cortical input areas elicits molecular alterations within granule cells of the dentate gyrus and behavioral abnormalities
Location: South Hall A
Presentation Time: Tuesday, Oct 20, 2009, 9:00 AM -10:00 AM
Authors: *J. A. HARRIS1,2, N. DEVIDZE1, M. T. THWIN1, T. HAMTO1, D. KIM1, K. HO1, G.-Q. YU1, L. MUCKE1,2;
1Gladstone Inst. Neurol Dis, San Francisco, CA; 2Neurol., UCSF, San Francisco, CA
Abstract: In Alzheimer’s disease (AD), granule cells of the dentate gyrus are vulnerable to APP/Aβ-induced molecular and functional impairments. Aβ may exert these effects within granule cells, extracellularly after being released from granule cells or synaptic contacts, or by affecting neurons in distant regions that provide afferent input to granule cells. Our goal is to identify where APP/Aβ first acts within the vulnerable entorhinal-hippocampal network to ultimately elicit network dysfunction and molecular and behavioral deficits. To dissect the role of APP/Aβ expression in different, but interconnected, brain regions, we used transgenic mice expressing APP primarily in layer II/III pyramidal cells of the medial entorhinal cortex (EC), which provides the primary excitatory afferent input to granule cells of the dentate gyrus. No APP expression was detected in dentate granule cells of these mice. At 4 and 9 months of age, transgenic mice showed significant alterations in several behavioral assays characteristic of other mouse models of AD, including hyperactivity in the open field, disinhibition in the elevated plus maze, and spatial memory deficits in the Morris water maze. At 6 months of age, transgenic mice had molecular alterations in granule cells that were previously shown to correlate with behavioral deficits in transgenic mice with panneuronal expression of APP, including reductions in calbindin and fos levels. In the transgenic mice with restricted APP expression, amyloid plaque deposition was already extensive at 6 months of age in cortical regions that expressed APP, but very little to no Aβ was deposited within the dentate gyrus at this age. These results suggest that molecular and functional deficits within granule cells of the hippocampus are due to a trans-synaptic effect of Aβ. Whether these deficits are due to a soluble, synaptically released species of Aβ acting directly on granule cells, or to changes in afferent input induced by Aβ in the entorhinal cortex remains to be determined. Understanding where Aβ first triggers network dysfunction may enable the design of new strategies to better protect the most vulnerable brain regions in AD patients.
Disclosures:  J.A. Harris , None; N. Devidze, None; M.T. Thwin, None; T. Hamto, None; D. Kim, None; K. Ho, None; G. Yu, None; L. Mucke, None.
Keyword(s): alzheimer's
entorhinal cortex
dentate gyrus
Support: NIA
[Authors]. [Abstract Title]. Program No. XXX.XX. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online.

2009 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.




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