Enhanced accumulation of phosphorylated alpha-synuclein in double transgenic mice expressing mutant beta-amyloid precursor protein and presenilin-1.

Abstract

A recent report showed that the accumulation of alpha-synuclein (alpha-syn) was detected in the brains of one-third of Alzheimer's disease and Down syndrome patients. However, the relationship between amyloid-beta protein (Abeta) and alpha-syn remains unclear. We analyzed the relation between the mutation of presenilin-1 (PS-1) and the pathological features of beta-amyloidosis and alpha-synucleinopathy. We generated doubly transgenic mice overexpressing mutant beta-amyloid precursor protein (betaAPP; Tg2576) and mutant PS-1 (PS1L286Vtg; line 198) and analyzed 19 double Tg betaAPP(+)/PS(+) mice at 5-23 months (young to old), 23 age-matched single Tg betaAPP(+)/PS(-) mice, and 11 non-Tg littermates. Immunohistochemical comparison was performed in these three groups by counting the area and the number of alpha-syn- or phosphorylated alpha-syn (palpha-syn)-positive dystrophic neurites per plaque (ASPDN, pASPDN). The acceleration of Abeta pathology was found with earlier onset and exaggerated numbers in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains. The accumulation of ASPDN and pASPDN was also accelerated in double Tg betaAPP(+)/PS(+) compared with single Tg betaAPP(+)/PS(-) mouse brains, especially in pASPDN. The number and area of alpha-syn and palpha-syn, and the ratio of palpha-syn positive neurites were significantly higher in double Tg betaAPP(+)/PS(+) than in single Tg betaAPP(+)/PS(-) mouse brains in middle-aged and old groups. Additional overexpression of mutant PS-1 accelerated Abeta-induced alpha-synucleinopathy and further facilitated the phosphorylation of alpha-syn, suggesting a direct association between mutant PS-1 and phosphorylation of alpha-syn.

• Authors: Tomoko Kurata, Takeshi Kawarabayashi, Tetsuro Murakami, Kazunori Miyazaki, Nobutoshi Morimoto, Yasuyuki Ohta, Yasushi Takehisa, Makiko Nagai, Masaki Ikeda, Etsuro Matsubara, David Westaway, Peter St George Hyslop, Yasuo Harigaya, Tatsushi Kamiya, Mikio Shoji, Koji Abe
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 85 Issue 10 Pg. 2246-52 (Aug 01 2007) ISSN: 0360-4012 [Print] United States
• PMID: 17526016 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• Amyloid beta-Protein Precursor
• Presenilin-1
• alpha-Synuclein

Topics

• Amyloid beta-Protein Precursor (genetics, metabolism)
• Amyloidosis (pathology)
• Animals
• Brain (metabolism, pathology)
• Cerebral Cortex (metabolism, pathology)
• Immunohistochemistry
• Mice
• Mice, Transgenic
• Mutation
• Neurites (metabolism, pathology)
• Phosphorylation
• Presenilin-1 (genetics, metabolism)
• Time Factors
• alpha-Synuclein (metabolism)