Progranulin haploinsufficiency reduces amyloid beta deposition Alzheimer’s disease model mice.

Masato Hosokawa, Yoshinori Tanaka, Tetsuaki Arai, Hiromi Kondo, Haruhiko Akiyama, Masato Hasegawa

Granulin (Grn) mutations were identified in familial frontotemporal lobar degeneration (FTLD) patients with TAR DNA-binding protein of 43 kd (TDP-43) pathology. Grn transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in FTLD pathogenesis. Moreover, recent findings indicate that Grn mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer's disease. To investigate the influence of PGRN on amyloid beta (Aβ) accumulation, amyloid precursor protein (APP) transgenic mice were interbred with Grn-deficient mice, producing APP transgenic mice harboring the Grn hemizygote (APP/Grn+/-). Brains were collected from 16-18-month-old APP and APP/Grn+/- mice and sequential extraction of proteins, immunoblotting and immunohistochemical analysis were performed. Immunohistochemical analysis showed that the number and area of Aβ plaque was significantly decreased in APP/Grn+/- mice as compared to APP mice. Immunoblotting analysis revealed that Aβ was reduced in the sarkosyl-insoluble fraction of 16-18-month-old APP/Grn+/- mice as compared with that of APP transgenic mice. Our data suggest that PGRN haploinsufficiency may decrease accumulation of Aβ.

Experimental Animals

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