Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer's disease.
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.
Epis
Roberta
R
Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, 20133 Milan, Italy.
Marcello
Elena
E
Gardoni
Fabrizio
F
Vastagh
Csaba
C
Malinverno
Matteo
M
Balducci
Claudia
C
Colombo
Alessio
A
Borroni
Barbara
B
Vara
Hugo
H
Dell'Agli
Mario
M
Cattabeni
Flamino
F
Giustetto
Maurizio
M
Borsello
Tiziana
T
Forloni
Gianluigi
G
Padovani
Alessandro
A
Di Luca
Monica
M
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000072197:ADAM10 Protein; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000074288:Discs Large Homolog 1 Protein; D004195:Disease Models, Animal; D051528:Guanylate Kinases; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D013569:Synapses / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C033652:postsynaptic density proteins; D051528:Guanylate Kinases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse