Enhanced accumulation of phosphorylated alpha-synuclein in double transgenic mice expressing mutant beta-amyloid precursor protein and presenilin-1.
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.
Kurata
Tomoko
T
Department of Neurology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Kawarabayashi
Takeshi
T
Murakami
Tetsuro
T
Miyazaki
Kazunori
K
Morimoto
Nobutoshi
N
Ohta
Yasuyuki
Y
Takehisa
Yasushi
Y
Nagai
Makiko
M
Ikeda
Masaki
M
Matsubara
Etsuro
E
Westaway
David
D
Hyslop
Peter St George
PS
Harigaya
Yasuo
Y
Kamiya
Tatsushi
T
Shoji
Mikio
M
Abe
Koji
K
D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000686:Amyloidosis / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D051844:alpha-Synuclein / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D051844:alpha-Synuclein