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

Abstract

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.