Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice

Bernardo, Alexandra; Harrison, Fiona E.; McCord, Meghan C.; Zhao, Jiali; Bruchey, Aleksandra K.; Davies, Sean S.; Roberts, L. Jackson; Mathews, Paul M.; Matsuoka, Yasuji; Ariga, Toshio; Yu, Robert K.; Thompson, Rebecca; McDonald, Michael P.

doi:10.1016/j.neurobiolaging.2007.12.022

Cited by 105 publications

(144 citation statements)

References 89 publications

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“…Previous studies report that APP/PS1 mice show reference memory impairments by 3 months of age and persist throughout life (Reiserer et al 2007;Bernardo et al 2009;O'Leary and Brown 2009). By comparing these results with our previous Y-maze test for behavioral analysis of 11-12-month-old APP/PS1 mice , we found that 24-month-old APP/PS1 cohorts show more severe working and reference memory impairment.…”

Section: Discussionsupporting

confidence: 60%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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Section: Discussionsupporting

confidence: 60%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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“…Thus, ganglioside alterations occurring in mice expressing the human mutant APP SL transgene with or without a PSEN1 mutation, but not with a PSEN1 mutation alone, are similar to those observed in humans with AD (23,28,39). In contrast to the robust changes in the cortex, only slight changes in the ganglioside pattern were found in the cerebellum in the PSEN1 and APP/PSEN1 mutant lines (40). Alterations in cerebellar gangliosides have not been reported in the cerebellum of AD brains, although b-series cerebellar gangliosides are reduced in normal aging (29) and a reduction in total cerebellar gangliosides has been reported in patients with DS (25).…”

Section: Ganglioside Metabolism In Admentioning

confidence: 55%

“…Although the amount of gangliosides and their patterns are similar in control and in AD cases (37), an observation was made that the A2B5 antibody reacted with human brain c-series gangliosides and, unexpectedly, sulfatides (38). The brain gangliosides of different transgenic mouse models of AD have been analyzed and compared with those of age-matched wild-type mice (39)(40)(41)(42). Barrier et al (39) observed a marked increase in the simple gangliosides GM2 and GM3 in the cortex of 2-year-old APP SL mice expressing the Swedish (K670N/M671L) and London (V717I) mutations of human APP.…”

Section: Ganglioside Metabolism In Admentioning

confidence: 99%

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Ariga

McDonald

2008

Journal of Lipid Research

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“…Although the consequences of huntingtin serine 16 phosphorylation on cell viability were not assessed in that study, it was proposed that phosphorylation at this amino acid residue might be important for toxicity mediated by mutant huntingtin fragments (46). Thus, the consequences of huntingtin phosphorylation at serine 16 on cell functions and viability might depend on whether only serine 16 (46) or both serine 13 and 16 (16,17,47, and this study) are phosphorylated, on protein context (full-length huntingtin versus N-terminal fragments) and, potentially, on the co-occurrence of other concomitant posttranslational modifications of mutant huntingtin (2,10,17,48). Elucidating the signaling pathways involved in regulating huntingtin posttranslational modifications and their cross-talk will be of utmost importance.…”

Section: Discussionmentioning

confidence: 94%

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

Pardo

Maglione

Alpaugh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

144

143

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Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis.H untington disease (HD) is an inherited neurodegenerative monogenic disorder caused by the expansion of a polyglutamine stretch beyond 36 residues in the amino-terminal domain of huntingtin (Htt), a protein expressed in most tissues and cells. The mutation causes huntingtin to acquire toxic conformation/s and to affect neuronal function and viability. Medium-sized spiny neurons in the corpus striatum are most affected, but neurodegeneration also occurs in the cerebral cortex and, to a minor extent, in other brain areas, resulting in motor and psychiatric symptoms, as well as cognitive decline.The cellular and molecular mechanisms underlying HD pathogenesis are complex. Both loss and gain of function of mutant huntingtin contribute to cause a wide array of neuronal dysfunctions affecting cell signaling, gene transcription, axonal transport, cell and mitochondrial metabolism as well as neurotransmission (1).In recent years, a breakthrough in HD research has been the discovery that posttranslational modifications of mutant Htt are crucial modulators of mutant Htt toxicity (2-4). Phosphorylation at various serine residues prevents cleavage of mutant huntingtin into more toxic fragments, decreases neural cell death in vitro (5-10), and/or restores Htt functions that are compromised by the mutation (8, 11). The most dramatic effects have been described for huntingtin phosphorylation at serine 13 and serine 16. These two amino acid residues are part of the highly conserved amino-terminal "N17" domain of huntingtin, a domain that regulates huntingtin intracellular localization and association to cellular membranes (12, 13), as well as kinetics of mutant huntingtin aggregation (14,15). Phosphomimetic mutations of serine 13 and serine 16 by aspartic or glutamic acid substitution (S13D and S16D or S13E and S16E) decrease the toxicity of mutant huntingtin fragments in vitro (10, 16). In line with these studies, expression of a phosphomimetic (S13D and S16D) mutant form of expanded full-length huntingtin in a BACHD transgenic mouse model was shown to result in a normal phenotype, with no detectable signs of HD pathology by 12 mo (17).These findings suggest that pharmacological interventions that modulate cell sig...

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Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice

Cited by 105 publications

References 89 publications

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

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