Article

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

ABSTRACT 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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    • "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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    • "Mouse models of both AD and DS exhibit seizures [4] [10]. Seizures in AD and DS may share a common pathogenetic basis in which the toxic accumulation of amyloid-β (Aβ) peptides triggers synaptic degeneration, circuit remodeling, and abnormal synchronization of neuronal networks [11]. "
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    ABSTRACT: The objective of this study was to determine the association of seizures and cognitive decline in adults with Down syndrome (DS) and Alzheimer's-type dementia. A retrospective data analysis was carried out following a controlled study of antioxidant supplementation for dementia in DS. Observations were made at baseline and every 6 months for 2 years. Seizure history was obtained from study records. The primary outcome measures comprised the performance-based Severe Impairment Battery (SIB) and Brief Praxis Test (BPT). Secondary outcome measures comprised the informant-based Dementia Questionnaire for Mentally Retarded Persons and Vineland Adaptive Behavior Scales. Because a large proportion of patients with seizures had such severe cognitive decline as to become untestable on the performance measures, time to "first inability to test" was measured. Adjustments were made for the potentially confounding co-variates of age, gender, APOE4 status, baseline cognitive impairment, years since dementia onset at baseline, and treatment assignment. The estimated odds ratio for the time to "first inability to test" on SIB comparing those with seizures to those without is 11.02 (95% CI: 1.59, 76.27), a ratio that is significantly different from 1 (p = 0.015). Similarly, we estimated an odds ratio of 9.02 (95% CI: 1.90, 42.85) on BPT, a ratio also significantly different than 1 (p = 0.006). Results from a secondary analysis of the informant measures showed significant decline related to seizures. We conclude that there is a strong association of seizures with cognitive decline in demented individuals with DS. Prospective studies exploring this relationship in DS are indicated.
    Journal of Alzheimer's disease: JAD 01/2012; 29(1):177-85. DOI:10.3233/JAD-2012-111613 · 4.15 Impact Factor
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    • "Audiogenic seizures have been observed in the rodent model (Ts65Dn) of DS and can be attenuated with antagonists to the metabotropic glutamate receptor 5 (mGluR5). These findings suggest that the amyloid precursor protein (APP), which is over-expressed in DS, may mediate this seizure susceptibility through the glutamate receptor (Westmark et al., 2009, 2010). Seizures in the temporal lobe may damage hippocampal circuitry, a situation which is worsened by the toxic accumulation of amyloid-β peptides seen in Alzheimer's disease (AD) (Noebels, 2011). "
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    ABSTRACT: This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40 years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations.
    Progress in brain research 01/2012; 197:101-21. DOI:10.1016/B978-0-444-54299-1.00006-6 · 5.10 Impact Factor
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