Alzheimer's Disease and Frontotemporal Dementia

Volume 670 of the series Methods in Molecular Biology pp 245-262


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

  • Jorge J. PalopAffiliated withDepartment of Neurology, Gladstone Institute of Neurological Disease, University of California, San Francisco
  • , Lennart MuckeAffiliated withGladstone Institute of Neurological Disease, University of California, San Francisco
  • , Erik D. RobersonAffiliated withDepartments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham

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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.

Key words

Hippocampus Dentate gyrus Granule cell Mossy fiber Hilus Neuropeptide Y NPY Calbindin Seizure Epilepsy Excitability GABA GABAergic sprouting Ectopic expression Excitatory Inhibitory Immunohistochemistry Alzheimer’s disease Biomarkers Immediate early gene Fos Arc Neuronal activity