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Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer's disease.

http://www.ncbi.nlm.nih.gov/pubmed/20805102

We describe here an innovative, non-transgenic animal model of Alzheimer's disease. This model mimics early stages of sporadic disease, which represents the vast majority of cases. The model was obtained by interfering with the complex between a disintegrin and metalloproteinase domain containing protein 10 (ADAM10), the main α-secretase candidate, and its partner, synapse-associated protein 97, a protein of the postsynaptic density-membrane associated guanylate kinase family. Association of ADAM10 with synapse-associated protein 97 governs enzyme trafficking and activity at synapses. Interfering with the ADAM10/synapse-associated protein 97 complex for 2 weeks by means of a cell-permeable peptide strategy is sufficient to shift the metabolism of the amyloid precursor protein towards amyloidogenesis and allows the reproduction of initial phases of sporadic Alzheimer's disease. After 2 weeks of treatment, we detected progressive Alzheimer's disease-like neuropathology, with an increase of β-amyloid aggregate production and of tau hyperphosphorylation, and a selective alteration of N-methyl-d-aspartic acid receptor subunit composition in the postsynaptic compartment of mouse brain. Behavioural and electrophysiological deficits were also induced by peptide treatment.

Pubmed ID: 20805102 RIS Download

Mesh terms: ADAM Proteins | Adaptor Proteins, Signal Transducing | Alzheimer Disease | Amino Acid Sequence | Amyloid Precursor Protein Secretases | Animals | Disease Models, Animal | Guanylate Kinase | Male | Membrane Proteins | Mice | Mice, Inbred C57BL | Molecular Sequence Data | Multiprotein Complexes | Nerve Tissue Proteins | Neural Inhibition | Protein Transport | Synapses | Time Factors

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Associated grants

  • Agency: Telethon, Id: GGP09196

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