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.

Department of Neurology, Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA, USA.
Methods in molecular biology (Clifton, N.J.) (Impact Factor: 1.29). 01/2011; 670:245-62. DOI: 10.1007/978-1-60761-744-0_17
Source: PubMed

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.

  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer’s disease. We wanted to determine if tau reduction may also be of benefit in intractable genetic epilepsies. Methods: We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage-gated sodium channel subunit Nav1.1. We genetically deleted one or two Tau alleles in mice carrying an Nav1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, EEG recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays. Results: Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug-induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only one Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance. Interpretation: Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies.
    Annals of Neurology 09/2014; 76(3). DOI:10.1002/ana.24230 · 11.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Considerable progress has been made in the past few years in the fight against Alzheimer's disease (AD) and Parkinson's disease (PD). Neuropathological studies in human brains and experimental in vivo and in vitro models support the notion that synapses are affected even at the earliest stages of the neurodegenerative process. The objective of this manuscript is to review some of the mechanisms of synaptic damage in AD and PD. Some lines of evidence support the notion that oligomeric neurotoxic species of amyloid β, α-synuclein, and Tau might contribute to the pathogenesis of synaptic failure at early stages of the diseases. The mechanisms leading to synaptic damage by oligomers might involve dysregulation of glutamate receptors and scaffold molecules that results in alterations in the axonal transport of synaptic vesicles and mitochondria that later on lead to dendritic and spine alterations, axonal dystrophy, and eventually neuronal loss. However, while some studies support a role of oligomers, there is an ongoing debate as to the exact nature of the toxic species. Given the efforts toward earlier clinical and preclinical diagnosis of these disorders, understanding the molecular and cellular mechanisms of synaptic degeneration is crucial toward developing specific biomarkers and new therapies targeting the synaptic apparatus of vulnerable neurons.
    Biochemical pharmacology 01/2014; DOI:10.1016/j.bcp.2014.01.015 · 4.25 Impact Factor