Enhanced accumulation of phosphorylated α-synuclein in double transgenic mice expressing mutant β-amyloid precursor protein and presenilin-1

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

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


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

Original languageEnglish
Pages (from-to)2246-2252
Number of pages7
JournalJournal of Neuroscience Research
Issue number10
Publication statusPublished - Aug 1 2007
Externally publishedYes


  • Alzheimer's disease
  • Phosphorylation
  • Presenilin-1
  • Synuclein
  • Transgenic mouse

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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