Alzheimer disease (AD) is characterized by excessive deposition of amyloid β-peptides (Aβ peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the α-secretase within the Aβ peptide sequence. Proteinases of the ADAM family (a disintegrin and metalloproteinase) are the main candidates as physiologically relevant α-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP [V717I] increased the secretion of the neurotrophic soluble α-secretase-released N-terminal APP domain (APPsα), reduced the formation of Aβ peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an α-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in α-secretase activity contributes to the development of AD. 1456The
During the preparation of this manuscript for publication, an error was introduced into the Results section, in the fourth sentence of the paragraph beginning with "The levels of the APP-derived soluble peptides Aβ40 and Aβ42 in brains of double-transgenic mice and APP [V717I] control animals at the age of 18 weeks were quantified by specific sandwich ELISAs." The correct sentence appears below. We regret this error.In line ADAM10-mo × APP [V717I] , Αβ40 and Aβ42 were reduced by 49% and 20%, and in line ADAM10-hi × APP [V717I] , by 39% and 29%, respectively.
Alzheimer disease (AD) is characterized by excessive deposition of amyloid β-peptides (Aβ peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the α-secretase within the Aβ peptide sequence. Proteinases of the ADAM family (a disintegrin and metalloproteinase) are the main candidates as physiologically relevant α-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP [V717I] increased the secretion of the neurotrophic soluble α-secretase-released N-terminal APP domain (APPsα), reduced the formation of Aβ peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an α-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in α-secretase activity contributes to the development of AD. 1456The
The amyloid precursor protein (APP) is a member of a protein family in mammals that includes the APP-like proteins APLP1 and APLP2 [1]. All APP ⁄ APLP family members are type I integral membrane proteins with large extracellular ectodomains and short cytoplasmic tails. Compared with APP, both APLPs are highly homologous in their amino acid sequence (e.g. APLP2 ⁄ APP 52% identical, 71% similar) [2] and are proteolytically processed in a similar way. The N-terminal ectodomains are released by a shedding enzyme [2,3], whereas the C-termini remain in the membrane [2,4,5] and can be further processed to release a cytoplasmic fragment with signaling properties [4,6,7].Further elucidation of APLP2-processing is of relevance with regard to the outstanding function of this protein, which was derived from knockout experiments. Whereas a double knockout of APP and APLP1 did not show severe phenotypic changes in mice, the combined knockout of APLP2 with both of the other APP family members resulted in postnatal lethality [8,9]. This shows that APLP2 and ⁄ or one of its proteolytic fragments are essential for normal development and Cleavage of the amyloid precursor protein (APP) within the amyloid-beta (Ab) sequence by the a-secretase prevents the formation of toxic Ab peptides. It has been shown that the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17) act as a-secretases and stimulate the generation of a soluble neuroprotective fragment of APP, APPsa. Here we demonstrate that the related APP-like protein 2 (APLP2), which has been shown to be essential for development and survival of mice, is also a substrate for both proteinases. Overexpression of either ADAM10 or TACE in HEK293 cells increased the release of neurotrophic soluble APLP2 severalfold. The strongest inhibition of APLP2 shedding in neuroblastoma cells was observed with an ADAM10-preferring inhibitor. Transgenic mice with neuron-specific overexpression of ADAM10 showed significantly increased levels of soluble APLP2 and its C-terminal fragments. To elucidate a possible regulatory mechanism of APLP2 shedding in the neuronal context, we examined retinoic acid-induced differentiation of neuroblastoma cells. Retinoic acid treatment of two neuroblastoma cell lines upregulated the expression of both APLP2 and ADAM10, thus leading to an increased release of soluble APLP2.Abbreviations ADAM, a disintegrin and metalloproteinase; ADAM10DN, catalytically inactive dominant negative mutant form of ADAM10; APLP1, APP-like protein 1; APLP2, APP-like protein 2; APLP2s, cleaved soluble APLP2; APP, amyloid precursor protein; BACE, b-site APP-cleaving enzyme; CS-GAG, chondroitin sulfate glycosaminoglycan; PKC, protein kinase C; PMA, phorbol-12-myristate-13-acetate; PVDF, poly(vinylidene difluoride); RA, retinoic acid; TACE, tumor necrosis factor-a converting enzyme.
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