α-Synuclein accumulation associated with presenilin-1 mutations

Takeshi Ikeuchi, Atsushi Ishikawa

Department of Molecular Neuroscience, Brain Research Institute, Niigata University

Presenilin 1 (PS1) mutations are the major cause of familial Alzheimer'srsquo;s disease (FAD). Over 100 different mutations in the PS1 gene have been described, and these are believed to lead disease through the alteration of amyloid precursor protein (APP) processing such that more of the amyloidogenic peptide Aβ42 is produced. Neuropathological hallmarks of both sporadic and familial AD are the deposition of Aβ-containing plaques and tau-positive neurofibrillary tangles. In addition to these pathological changes, substantial amounts of Lewy bodies have been reported to be found in the brain of the patients with AD. Recently, several PS1 mutations including a deletion at codon 440 (ΔT440), S170S, E184D, and M233V, were reported to show marked cortical Lewy bodies, which fulfils the diagnostic criteria for neocortical type of Lewy body disease. Interestingly, cotton-wool type of Aβ accumulation was frequently observed in brains of these cases. These observations offer the opportunity to understand the mechanisms involved in formation of the Aβ aggregation and Lewy bodies consisting of α-synuclein. It may be postulated that Lewy body formation is a downstream event from Aβ42 overproduction by APP processing by the PS1 mutants. However, there still remains a possibility that PS1 may have a direct effect on phosphorylation or degradation of α-synuclein by unknown mechanisms. Cell culture experiments or animal models should be studied to investigate the link between the PS1 mutants and α-synuclein accumulation at a molecular level.

Address correspondence to Dr. Takeshi Ikeuchi, Department of Molecular Neuroscience, Brain Research Institute, Niigata University (1 Asahimachi, Niigata 951-8585, Japan)