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The Journal of Neuroscience, April 5, 2006, 26(14):3845-3854; doi:10.1523/JNEUROSCI.5384-05.2006

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Neurobiology of Disease
Deletion of Presenilin 1 Hydrophilic Loop Sequence Leads to Impaired -Secretase Activity and Exacerbated Amyloid Pathology

Yu Deng,¹ Leonid Tarassishin,⁴ Verena Kallhoff,^1,2 Erica Peethumnongsin,^1,3 Ling Wu,¹ Yue-Ming Li,⁴ and Hui Zheng^1,2,3

¹Huffington Center on Aging, ²Department of Molecular and Human Genetics, and ³Interdepartmental Program of Cellular and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, and ⁴Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Correspondence should be addressed to Hui Zheng, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, M320, Houston, TX 77030. Email: huiz{at}bcm.tmc.edu

-Secretase processing of the amyloid precursor protein (APP) generates A₄₀ and A₄₂, peptides that constitute the principal components of the -amyloid plaque pathology of Alzheimer's disease (AD). The -secretase activity is executed by a high-molecular-weight complex of which presenilin 1 (PS1) is an essential component. PS1 is a multi-pass membrane protein, and the large hydrophilic loop domain between transmembrane domains 6 and 7 has been shown to interact with various proteins. To determine the physiological function of the loop domain, we created a strain of PS1 knock-in mice in which the exon 10, which encodes most of the hydrophilic loop sequence, was deleted from the endogenous PS1 gene. We report here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced -secretase cleavage at the A₄₀, but not the A₄₂, site. Surprisingly, this reduction of A₄₀ is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in -secretase processing, and decreased A₄₀, not increased A₄₂ is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of A₄₀ against amyloid pathology and raises the possibility that impaired -secretase activity could be the basis for AD pathogenesis in general.

Key words: Alzheimer's disease; amyloid peptides; -secretase; presenilin; knock-in mice; homodimer

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Received Dec. 16, 2005; revised Feb. 2, 2006; accepted Feb. 24, 2006.

Correspondence should be addressed to Hui Zheng, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, M320, Houston, TX 77030. Email: huiz{at}bcm.tmc.edu

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