{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:05:54Z","timestamp":1791266754005,"version":"4.1.0"},"reference-count":38,"publisher":"Society for Neuroscience","issue":"48","license":[{"start":{"date-parts":[[2008,5,28]],"date-time":"2008-05-28T00:00:00Z","timestamp":1211932800000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2007,11,28]]},"abstract":"<jats:p>Mutations in the<jats:italic>PSEN1<\/jats:italic>gene encoding presenilin 1 (PS1) are linked to a vast majority of pedigrees with early-onset, autosomal dominant forms of familial Alzheimer's disease (FAD). Lewy body (LB) pathology is frequently found in the brains of FAD patients harboring<jats:italic>PSEN1<\/jats:italic>mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (\u0394T440) in a familial case diagnosed as having the neocortical type of dementia with LBs (DLB) and variant AD. In this report, we investigated the possible involvement of PS1 \u0394T440 mutation in aberrant \u03b1-synuclein accumulation. We established cell lines that stably express either wild-type (WT) PS1 or the FAD-linked PS1 H163R, E280A, \u0394E9, and PS1 \u0394T440 mutants and now demonstrate that the expression of the PS1 \u0394T440 mutant led to a marked elevation in the ratio of \u03b2-amyloid (A\u03b2) 42\/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated \u03b1-synuclein increase in neuronal and non-neuronal cells expressing the PS1 \u0394T440 mutant compared with cells that express WT PS1 or the PS1 H163R and E280A variants that are not associated with LB pathology. This finding is consistent with our demonstration of elevated levels of phosphorylated \u03b1-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 \u0394T440 mutation. These observations raise the intriguing suggestion that the mechanism(s) by which the PS1 \u0394T440 mutant causes DLB and variant AD are by enhancing the phosphorylation of \u03b1-synuclein and the ratio of A\u03b2<jats:sub>42\/40<\/jats:sub>peptides, respectively, in the brain.<\/jats:p>","DOI":"10.1523\/jneurosci.4244-07.2007","type":"journal-article","created":{"date-parts":[[2007,11,28]],"date-time":"2007-11-28T17:28:46Z","timestamp":1196270926000},"page":"13092-13097","source":"Crossref","is-referenced-by-count":39,"title":["Enhanced Accumulation of Phosphorylated \u03b1-Synuclein and Elevated \u03b2-Amyloid 42\/40 Ratio Caused by Expression of the Presenilin-1 \u0394T440 Mutant Associated with Familial Lewy Body Disease and Variant Alzheimer's 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