Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia.
Progranulin haploinsufficiency causes frontotemporal dementia with tau-negative, ubiquitin-positive neuronal inclusion pathology. In this study, we showed that progranulin-deficient mice displayed increased depression- and disinhibition-like behavior, as well as deficits in social recognition from a relatively young age. These mice did not have any deficit in locomotion or exploration. Eighteen-month-old progranulin-deficient mice demonstrated impaired spatial learning and memory in the Morris water maze. In addition to behavioral deficits, progranulin-deficient mice showed a progressive development of neuropathology from 12 mo of age, including enhanced activation of microglia and astrocytes and ubiquitination and cytoplasmic accumulation of phosphorylated TDP-43. Thus, progranulin deficiency induced FTD-like behavioral and neuropathological deficits. These mice may serve as an important tool for deciphering underlying mechanisms in frontotemporal dementia.
Yin
Fangfang
F
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
Dumont
Magali
M
Banerjee
Rebecca
R
Ma
Yao
Y
Li
Huihong
H
Lin
Michael T
MT
Beal
M Flint
MF
Nathan
Carl
C
Thomas
Bobby
B
Ding
Aihao
A
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D000077155:Granulins; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D000077153:Progranulins
D004268:DNA-Binding Proteins; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins