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The Journal of Neuroscience, August 8, 2007, 27(32):8496-8504; doi:10.1523/JNEUROSCI.1008-07.2007

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Neurobiology of Disease
Effects of Alzheimer's Disease on Different Cortical Layers: The Role of Intrinsic Differences in Aß Susceptibility

Rita R. Romito-DiGiacomo,¹ Harry Menegay,³ Samantha A. Cicero,² and Karl Herrup¹

¹Department of Neuroscience, Alzheimer Research Laboratory, and ²Department of Pharmacology, Case School of Medicine, Cleveland, Ohio 44106, and ³University Memory and Aging Center, Fairhill Center, Cleveland, Ohio 44120

Correspondence should be addressed to Karl Herrup at the above address. Email: herrup{at}biology.rutgers.edu

Alzheimer's disease is late life dementia associated with significant neurodegeneration in both cortical and subcortical regions. During the 10 year course of the disease, neurons are lost in a progressive pattern that is relatively consistent among individuals. One example of this is the progression of disease pathology found in both the neocortex and archicortex. In these structures, the earliest problems can be found in superficial cortical layers (II–IV), whereas later the disease advances to involve the deeper cortical layers (V–VI). It is unclear whether these apparent differences in sensitivity are intrinsic to the neurons or imposed by external factors such as the pattern of connections. We used ß-amyloid (Aß) peptide treatment of cultured mouse neurons as our model system. We show first that, as in hippocampus, dissociated cultures of embryonic cortical neurons are biased toward the survival of cells that were finishing division in the ventricular zone at the time of harvest. Thus, embryonic day 13.5 (E13.5) cultures contain primarily deep-layer neurons whereas E16.5 cultures contain cells destined for upper layers. We use this cell-type specific segregation to our advantage and show, using both differences in gene expression profiles and Aß survival curves, that deeper layer neurons are significantly more resistant to the toxic effects of Aß than are cells from the more superficial strata. This suggests that an intrinsic underlying biology drives at least part of the AD progression pattern and that the time of harvest is a crucial variable in the interpretation of any cortical culture experiment.

Key words: expression array; cell culture; rodent; neocortex; Aß peptide; neuronal death

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Received Oct. 4, 2006; revised June 20, 2007; accepted June 20, 2007.

Correspondence should be addressed to Karl Herrup at the above address. Email: herrup{at}biology.rutgers.edu

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