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Inhibition of Alzheimer's disease beta-amyloid aggregation, neurotoxicity and in vivo deposition

INHIBITION OF ALZHEIMER'S DISEASE b-AMYLOID AGGREGATION, NEUROTOXICITY AND IN VIVO DEPOSITION**Supported by Howard Hughes Medical Institute, CNPq, FAPERJ. E-mail: ferreira@bioqmed.ufrj.br

FERNANDA G. DE FELICE1, JEAN-CHRISTOPHE C. HOUZEL2, JOSÉ GARCIA-ABREU2, PAULO R. LOUZADA1, ROSENILDE C. AFONSO2, MARIA NAZARÉ MEIRELLES3, ROBERTO LENT2, VIVALDO MOURA NETO2AND SERGIO T. FERREIRA1

1

2Dept. of Anatomy, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro.

3FIOCRUZ, RJ, Brazil

Aggregation of amyloid b peptide (Ab) into fibrils and deposition as senile plaques are primarily related to neurotoxicity in Alzheimer's Disease (AD). Thus, agents interfering with aggregation may be potentially useful in preventing or decreasing Ab toxicity. We first studied the effects of guanidine hydrochloride and temperature on the stability of fibrillar Ab using peptides truncated at different positions. These experiments suggested that hydrophobic interactions mediated by the C-terminal portion of Ab are important for fibril stability. Based on these results, we found two compounds capable of disaggregating amyloid fibrils at micromolar concentrations, as indicated by light scattering measurements and transmission electron microscopy. When applied to primary cultures of E18 rat hippocampal neurons, both drugs significantly reduced Ab-induced cell death (as assayed by trypan blue exclusion). One of the drugs was also tested in an in vivo model of cerebral amyloid deposition. Ab was microinjected into the hippocampus of rats in the absence or in the presence of the drug. After 8 days, brain sections were stained with thioflavin-S and the area occupied by amyloid deposits was quantified by image analysis, revealing a marked reduction in amyloid deposition in the presence of the drug. These results raise the possibility that these compounds, or derivatives prepared from them, may be effective in preventing Ab neurotoxicity and brain deposition in AD. — ( June 27, 2000 ).

  • *
    Supported by Howard Hughes Medical Institute, CNPq, FAPERJ.
    E-mail:
  • Publication Dates

    • Publication in this collection
      05 Oct 2000
    • Date of issue
      Sept 2000
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