Intracranial v. cholerae sialidase protects against excitotoxic neurodegeneration

Anandh Dhanushkodi, Michael Mcdonald

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Converging evidence shows that GD3 ganglioside is a critical effector in a number of apoptotic pathways, and GM1 ganglioside has neuroprotective and noötropic properties. Targeted deletion of GD3 synthase (GD3S) eliminates GD3 and increases GM1 levels. Primary neurons from GD3S-/- mice are resistant to neurotoxicity induced by amyloid-β or hyperhomocysteinemia, and when GD3S is eliminated in the APP/PSEN1 double-transgenic model of Alzheimer's disease the plaque-associated oxidative stress and inflammatory response are absent. To date, no small-molecule inhibitor of GD3S exists. In the present study we used sialidase from Vibrio cholerae (VCS) to produce a brain ganglioside profile that approximates that of GD3S deletion. VCS hydrolyzes GD1a and complex b-series gangliosides to GM1, and the apoptogenic GD3 is degraded. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. Sensorimotor behaviors, anxiety, and cognition were unaffected in VCS-treated mice. To determine whether VCS was neuroprotective in vivo, we injected kainic acid on the 25th day of infusion to induce status epilepticus. Kainic acid induced a robust lesion of the CA3 hippocampal subfield in aCSF-treated controls. In contrast, all hippocampal regions in VCS-treated mice were largely intact. VCS did not protect against seizures. These results demonstrate that strategic degradation of complex gangliosides and GD3 can be used to achieve neuroprotection without adversely affecting behavior.

Original languageEnglish (US)
Article numbere29285
JournalPLoS One
Volume6
Issue number12
DOIs
StatePublished - Dec 15 2011

Fingerprint

gangliosides
cholera
sialidase
Gangliosides
Cholera
Kainic Acid
Neuraminidase
G(M1) Ganglioside
Oxidative stress
Amyloid
Neurons
mice
Brain
Hyperhomocysteinemia
Third Ventricle
Vibrio cholerae
Status Epilepticus
Degradation
Cognition
Molecules

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Intracranial v. cholerae sialidase protects against excitotoxic neurodegeneration. / Dhanushkodi, Anandh; Mcdonald, Michael.

In: PLoS One, Vol. 6, No. 12, e29285, 15.12.2011.

Research output: Contribution to journalArticle

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