Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer's disease.

Abstract

Mutations in the PSEN1 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 PSEN1 mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (deltaT440) 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 deltaT440 mutation in aberrant alpha-synuclein accumulation. We established cell lines that stably express either wild-type (WT) PS1 or the FAD-linked PS1 H163R, E280A, deltaE9, and PS1 deltaT440 mutants and now demonstrate that the expression of the PS1 deltaT440 mutant led to a marked elevation in the ratio of beta-amyloid (Abeta) 42/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated alpha-synuclein increase in neuronal and non-neuronal cells expressing the PS1 deltaT440 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 alpha-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 deltaT440 mutation. These observations raise the intriguing suggestion that the mechanism(s) by which the PS1 deltaT440 mutant causes DLB and variant AD are by enhancing the phosphorylation of alpha-synuclein and the ratio of Abeta(42/40) peptides, respectively, in the brain.

• Authors: Hiroyuki Kaneko, Akiyoshi Kakita, Kensaku Kasuga, Hiroaki Nozaki, Atsushi Ishikawa, Akinori Miyashita, Ryozo Kuwano, Genta Ito, Takeshi Iwatsubo, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Sangram S Sisodia, Takeshi Ikeuchi
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 27 Issue 48 Pg. 13092-7 (Nov 28 2007) ISSN: 1529-2401 [Electronic] United States
• PMID: 18045903 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• PSEN1 protein, human
• Presenilin-1
• Receptors, Notch
• alpha-Synuclein
• Threonine

Topics

• Aged
• Alzheimer Disease (genetics)
• Amyloid beta-Peptides (metabolism)
• Animals
• Cell Line, Tumor
• Enzyme-Linked Immunosorbent Assay (methods)
• Gene Expression Regulation (genetics)
• Glioma
• Humans
• Lewy Body Disease (genetics)
• Mice
• Middle Aged
• Mutation (genetics)
• Neuroblastoma
• Phosphorylation
• Presenilin-1 (genetics)
• Rats
• Receptors, Notch (metabolism)
• Threonine (genetics)
• Transfection (methods)
• alpha-Synuclein (metabolism)