gamma-Secretase processing of the amyloid precursor protein (APP) generates Abeta40 and Abeta42, peptides that constitute the principal components of the beta-amyloid plaque pathology of Alzheimer's disease (AD). The gamma-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 gamma-secretase cleavage at the Abeta40, but not the Abeta42, site. Surprisingly, this reduction of Abeta40 is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in gamma-secretase processing, and decreased Abeta40, not increased Abeta42 is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of Abeta40 against amyloid pathology and raises the possibility that impaired gamma-secretase activity could be the basis for AD pathogenesis in general.
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