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Enhanced accumulation of phosphorylated α‐synuclein in double transgenic mice expressing mutant β‐amyloid precursor protein and presenilin‐1
Author(s) -
Kurata Tomoko,
Kawarabayashi Takeshi,
Murakami Tetsuro,
Miyazaki Kazunori,
Morimoto Nobutoshi,
Ohta Yasuyuki,
Takehisa Yasushi,
Nagai Makiko,
Ikeda Masaki,
Matsubara Etsuro,
Westaway David,
Hyslop Peter St. George,
Harigaya Yasuo,
Kamiya Tatsushi,
Shoji Mikio,
Abe Koji
Publication year - 2007
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21352
Subject(s) - presenilin , amyloid precursor protein , genetically modified mouse , mutant , phosphorylation , neurite , chemistry , microbiology and biotechnology , transgene , synuclein , alzheimer's disease , alpha synuclein , biology , medicine , biochemistry , parkinson's disease , in vitro , gene , disease
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. © 2007 Wiley‐Liss, Inc.