Abstract
High levels of Aβ impair neuronal function at least in part by disrupting normal synaptic transmission and causing dysfunction of neural networks. This network dysfunction includes abnormal synchronization of neuronal activity resulting in epileptiform activity. Over time, this aberrant network activity can lead to the depletion of calcium-dependent proteins, such as calbindin, Fos, and Arc, and compensatory inhibitory remodeling of hippocampal circuits, including GABAergic sprouting and ectopic expression of the inhibitory neuropeptide Y (NPY) in dentate granule cells. Here we present detailed protocols for detecting and quantifying these alterations in mouse models of Alzheimer’s disease (AD) by immunohistochemistry. These methods are useful as surrogate measures for detecting chronic aberrant network activity in models of AD and epilepsy. In addition, since we have found that the severity of these changes relates to the degree of Aβ-dependent cognitive impairments, the protocols are useful for quantifying biomarkers of cognitive impairment in mouse models of AD.
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Acknowledgments
We thank members of the Mucke laboratory, particularly Nga Bien-Ly and Alice Thwin, who helped develop these protocols; Jeannie Chin, Irene Cheng, and Julie Harris for helpful comments on the manuscript; Paul Worley for Arc antibody; and Stephen Ordway and Gary Howard for editorial review. This work was supported by Stephen D. Bechtel Jr. Young Investigator Awards (J.J.P and E.D.R), and NIH grants NS054811 (E.D.R.), AG023501 (L.M.) and AG022074 (L.M.).
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Palop, J.J., Mucke, L., Roberson, E.D. (2010). Quantifying Biomarkers of Cognitive Dysfunction and Neuronal Network Hyperexcitability in Mouse Models of Alzheimer’s Disease: Depletion of Calcium-Dependent Proteins and Inhibitory Hippocampal Remodeling. In: Roberson, E. (eds) Alzheimer's Disease and Frontotemporal Dementia. Methods in Molecular Biology, vol 670. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-744-0_17
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DOI: https://doi.org/10.1007/978-1-60761-744-0_17
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