Alzheimer's Disease and Down Syndrome Rodent Models Exhibit Audiogenic Seizures

Department of Pathology & Laboratory Medicine and Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, WI 53705, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 04/2010; 20(4):1009-13. DOI: 10.3233/JAD-2010-100087
Source: PubMed


Amyloid-beta protein precursor (AbetaPP) is overexpressed in Alzheimer's disease (AD), Down syndrome (DS), autism, and fragile X syndrome. Seizures are a common phenotype in all of these neurological disorders, yet the underlying molecular mechanism(s) of seizure induction and propagation remain largely unknown. We demonstrate that AD (Tg2576) and DS (Ts65Dn) mice exhibit audiogenic seizures, which can be attenuated with antagonists to metabotropic glutamate receptor 5 (mGluR5) or by passive immunization with anti-amyloid-beta antibody. Our data strongly implicates AbetaPP or a catabolite in seizure susceptibility and suggests that mGluR5 mediates this response.

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    • "Our research has examined audiogenic-induced seizure (AGS) incidence after chronic treatment with mGluR5 antagonists in several transgenic mouse lines (35, 36). In pursuit of these objectives, we incorporated the mGluR5 antagonist fenobam into a purified ingredient, soy-free diet that was matched to our standard lab chow (Purina 5015) for protein, fat, and carbohydrate content. "
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    ABSTRACT: Numerous neurological disorders including fragile X syndrome, Down syndrome, autism, and Alzheimer's disease are co-morbid with epilepsy. We have observed elevated seizure propensity in mouse models of these disorders dependent on diet. Specifically, soy-based diets exacerbate audiogenic-induced seizures in juvenile mice. We have also found potential associations between the consumption of soy-based infant formula and seizure incidence, epilepsy comorbidity, and autism diagnostic scores in autistic children by retrospective analyses of medical record data. In total, these data suggest that consumption of high levels of soy protein during postnatal development may affect neuronal excitability. Herein, we present our theory regarding the molecular mechanism underlying soy-induced effects on seizure propensity. We hypothesize that soy phytoestrogens interfere with metabotropic glutamate receptor signaling through an estrogen receptor-dependent mechanism, which results in elevated production of key synaptic proteins and decreased seizure threshold.
    Frontiers in Neurology 09/2014; 5:169. DOI:10.3389/fneur.2014.00169
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    • "Synaptic deficits in Tsc2 and Fmr1 mutant mice are corrected by treatments that modulate mGluR5 in opposite directions and disappear in mice that carry both mutations (Auerbach et al., 2011). Similarly, “too much” or “too little” APP and Aβ in Fmr1KO mice exacerbates audiogenic seizures (Westmark et al., 2010, 2013). These data support the requirement for maintenance of homeostatic levels of key synaptic proteins in the treatment of FXS and suggest that therapeutic dosages need to be tightly regulated. "
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    ABSTRACT: Fragile X syndrome (FXS) is a debilitating genetic disorder with no cure and few therapeutic options. Excessive signaling through metabotropic glutamate receptor 5 in FXS leads to increased translation of numerous synaptic proteins and exaggerated long-term depression. Two of the overexpressed proteins are amyloid-beta protein precursor (APP) and its metabolite amyloid-beta, which have been well-studied in Alzheimer's disease (AD). Here we discus the possibility that pharmaceuticals under study for the modulation of these proteins in AD might be viable therapeutic strategies for FXS. Specifically, a recently identified acetyltransferase inhibitor that reduces the levels and activity of β-site APP cleaving enzyme (BACE-1) has strong potential to attenuate BACE-1 activity and maintain homeostatic levels APP catabolites in FXS.
    Frontiers in Cellular Neuroscience 05/2013; 7:77. DOI:10.3389/fncel.2013.00077 · 4.29 Impact Factor
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    • "Genetic knockout of one App allele in Fmr1 KO mice attenuated AGS by 54% suggesting that overexpression of A␤PP and A␤ in an FMRP null background is an important contributing factor to seizure propensity [9]. The FRAXAD mice, which are a cross between the Tg2576 and Fmr1 KO and thus overexpress both human and mouse A␤PP, exhibit an additive effect on seizure propensity [7], which is reduced by soy restriction. However, Fmr1 KO /APP KO mice, which lack expression of both A␤PP and FMRP, exhibited the highest rates of wild running, seizures, and death of all of the strains tested. "
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    ABSTRACT: Seizures are a common phenotype in many neurological disorders including Alzheimer's disease, Down syndrome, and fragile X syndrome. Mouse models of these disorders overexpress amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) and are highly susceptible to audiogenic-induced seizures (AGS). We observed decreased AGS in these mice fed a casein-based, purified diet (D07030301) as opposed to a standard soy protein-containing, non-purified diet (Purina 5015). Our objective in this manuscript was to determine if soy protein, and in particular soy isoflavones, in the Purina 5015 were contributing to the seizure phenotype. Wild running, AGS, and death rates were assessed in juvenile mice fed Purina 5015, D07030301, D07030301 containing soy protein, or D07030301 supplemented with individual isoflavones (750 mg/kg daidzein or genistein). A short treatment (3 days) with Purina 5015 induced wild running and AGS in Alzheimer's disease mice. A 3-day treatment with daidzein-supplemented diet, but not genistein, induced wild running in wild type mice. To understand the mechanism underlying daidzein activity, we assessed dendritic AβPP expression in primary, cultured, wild type neurons treated with daidzein or genistein. In vitro, daidzein significantly increased dendritic AβPP. Thus, the soy isoflavone daidzein recapitulated seizure induction in vivo and altered AβPP expression in vitro. These results have important implications for individuals on soy-based diets as well as for rodent model research.
    Journal of Alzheimer's disease: JAD 10/2012; 33(3). DOI:10.3233/JAD-2012-121426 · 4.15 Impact Factor
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