Shedding the epilepsy comorbidity in Alzheimer's disease.

نویسنده

  • Elizabeth M Powell
چکیده

Commentary Epilepsy is a comorbidity in patients with Alzheimer's disease (AD). The cleavage of amyloid precursor protein (APP) by β-and γ-secretases produces amyloid β peptides, which are the main component of amyloid plaques. Alternatively, APP may be cleaved by an α-secretase to form the soluble fragment sAPPα, which promotes neuronal survival. Shifting the prote-olysis of APP from the amyloidogenic pathway to α-secretase generation is a potential therapeutic strategy for AD and associated epilepsy. Molecules that remove extracellular domains from trans-membrane proteins are collectively known as " sheddases, " and the largest family is the ADAM (a disintegrin and metalloprote-ase) family. Based on expression patterns and transgenic mouse studies, ADAM10 protein (also known as CD156c) has been proposed to be the main α-secretase in the generation of sAPPα. In overexpression studies, ADAM10 is neuroprotective in mice that overexpress APP in the kainate seizure model (1) and reduces β-amyloid deposition and cognitive dysfunction. However, total loss of the Adam10 gene in the mouse is embryonic lethal (2), and conditional deletions targeted to forebrain neuroprogeni-tors severely disrupted brain development, terminating in late embryonic mortality and intracranial hemorrhages (3). Thus, the role of ADAM10 as the α-secretase in the processing of APP in adult animal models could not be ascertained. The postnatal function of ADAM10 is revealed by using a neuronal specific Cre-loxP strategy with the Adam10 floxed mouse bred with the CamKIIα-Cre driver mouse strain (4). The expression of CamKIIα commences at postnatal day 5 (P5), circumventing the embryonic and perinatal lethality of the previous mouse models. Based on CamKIIα expression patterns, ADAM10 was expected to be eliminated from the ce-rebral cortex, hippocampus, olfactory bulb, and amygdala, and to a lesser extent in the striatum, thalamus, and hypothalamus. Many of the Adam10/CamKIIα conditional mutant mice died around P18–P27, during the time of synaptogenesis, while some mice lived to 2 months, but they were smaller in size and weight than their control littermates. Repetitive behavioral seizures were observed as early as P14, with some cases being tonic seizures that ended with respiratory distress and death. Depth electrodes implanted into the hippocampus recorded electrographic seizures in 20 percent of the Adam10/CamKIIa conditional mutant mice and in none of the control mice. In summary, genetic deletion of Adam10 retarded growth and initiated a seizure phenotype. During normal ontogeny, ADAM10 levels increase with postnatal age, in particular throughout synaptogenesis. The levels of ADAM10 in the targeted genetic …

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عنوان ژورنال:
  • Epilepsy currents

دوره 14 4  شماره 

صفحات  -

تاریخ انتشار 2014