ABSTRACT
Amyloid beta protein (Abeta) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Abeta is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Abeta to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Abeta bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Abeta neurotoxicity suggested that Abeta neurotoxicity involves APP. Thus Abeta toxicity may be mediated by the interaction of fibrillar Abeta with neuronal membrane proteins, notably APP. An Abeta-APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.
Subject(s)
Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/toxicity , Amyloid beta-Protein Precursor/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/isolation & purification , Amyloid beta-Protein Precursor/genetics , Animals , Biopolymers/chemistry , Biopolymers/isolation & purification , Biopolymers/metabolism , Biopolymers/toxicity , Cell Membrane/drug effects , Cell Membrane/metabolism , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Cerebral Cortex/pathology , Gene Deletion , Hippocampus/cytology , Hippocampus/embryology , Hippocampus/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Plaque, Amyloid/chemistry , Plaque, Amyloid/drug effects , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Protein Binding , Rats , SolubilityABSTRACT
We show here that antisense MAP2 oligonucleotides inhibit neurite outgrowth in cultured cerebellar macroneurons. Unlike control neurons, which first extend a lamellipodial veil followed by a consolidation phase during which the cells extend minor neurites, MAP2-suppressed cells persist with lamellipodia and later become rounded. The induction of microtubules containing tyrosinated tubulin, which parallels neurite outgrowth in control neurons, was blocked under antisense conditions. The small but significant increase in acetylated microtubules was not affected. In contrast, the suppression of tau, which selectively blocks axonal elongation, completely prevented the increase of acetylated microtubules, but did not modify the induction of labile microtubules. These results suggest that MAP2 and tau have different functions: the initial establishment of neurites depends upon MAP2, whereas further neurite elongation depends upon tau and microtubule stabilization.
