ABSTRACT
A major feature of Alzheimer's disease is the accumulation of ß-amyloid (Aß) peptide in the brain. Recent studies have indicated that Aß oligomers (Aßo) can interact with the cellular prion protein (PrPc). Therefore, this interaction might be driving some of Aß toxic effects in the synaptic region. In the present study, we report that Aßo binds to PrPc in the neuronal membrane playing a role on toxic effects induced by Aß. Phospholipase C-enzymatic cleavage of PrPc from the plasma membrane attenuated the association of Aßo to the neurons. Furthermore, an anti-PrP antibody (6D11) decreased the association of Aßo to hippocampal neurons with a concomitant reduction in Aßo and PrPc co-localization. Interestingly, this antibody blocked the increase in membrane conductance and intracellular calcium induced by Aßo. Thus, the data indicate that PrPc plays a role on the membrane perforations produced by Aßo, the increase in calcium ions and the release of synaptic vesicles that subsequently leads to synaptic failure. Future studies blocking Aßo interaction with PrPc could be important for the discovery of new therapeutic strategies for Alzheimer's disease.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/toxicity , Cell Membrane/pathology , PrPC Proteins/toxicity , Synapses/pathology , Amyloid beta-Peptides/physiology , Animals , Calcium/metabolism , Cells, Cultured , Female , Hippocampus/cytology , Molecular Targeted Therapy , Neurons/pathology , PrPC Proteins/physiology , Pregnancy , Protein Interaction Domains and Motifs , Synapses/metabolism , Synaptic Vesicles/metabolismABSTRACT
Prions, the etiological agents for infectious degenerative encephalopathies, act by entering the cell and inducing conformational changes in PrPC (a normal cell membrane sialoglycoprotein), which result in cell death. A specific cell-surface receptor to mediate PrPC and prion endocytosis has been predicted. Complementary hydropathy let us generate a hypothetical peptide mimicking the receptor binding site. Antibodies raised against this peptide stain the surface of mouse neurons and recognize a 66-kDa membrane protein that binds PrPC both in vitro and in vivo. Furthermore, both the complementary prion peptide and antiserum against it inhibit the toxicity of a prion-derived peptide toward neuronal cells in culture. Such reagents might therefore have therapeutic applications.