Abeta Oligomers and mechanisms of Neuronal Cell Death in Alzheimer's Disease

NIH R21 AG049693

The beta amyloid peptide (Abeta) is the primary component of the senile plaques observed in the brains of Alzheimer's patients, and this peptide is toxic to neurons and other cells in many different contexts, including expression in C. elegans (Link, 1995).  Despite many years of study, the mechanism(s) and disease relevance of Abeta toxicity remains unresolved.  Our current studies center around our characterization of a variant Abeta peptide that has a single amino acid substitution (leucine substituted for glycine at position 37, or G37L), which we found dramatically reduces the toxicity of Abeta in C. elegans and mammalian neuronal cultures (Fonte et al, 2011).  We propose that a primary mechanism of Abeta toxicity is the formation of membrane-damaging oligomers, which is blocked by the G37L substitution.  Our unpublished data suggests that the ability of Abeta to perturb membranes may not be an "accident", but may reflect a selected function related to the ability of Abeta to modulate the innate immune system.

Cultured hippocampal neurons treated with wild type, but not G37L, Abeta show induction of phospho-tau. (From Fonte et al, 2011)

Cultured hippocampal neurons treated with wild type, but not G37L, Abeta show induction of phospho-tau. (From Fonte et al, 2011)

C. elegans worms fed E. coli expressing wild type, but not G37L, Abeta show induction of endosomes associated with membrane repai.

C. elegans worms fed E. coli expressing wild type, but not G37L, Abeta show induction of endosomes associated with membrane repair.