Lysosomal gene Hexb displays haploinsufficiency in a knock-in mouse model of Alzheimer’s disease

IBRO Neuroscience Reports

Leanne K. Hein¹  Célia Fourrier²  Kim M. Hemsley³  Julien Bensalem³  John J. Hopwood³  Sofia Hassiotis³  Adeline A. Lau³  Kathryn J. Hattersley⁴  Paul J. Trim⁵  Timothy J. Sargeant⁵  Lauren S. Whyte⁵ 

[1] Childhood Dementia Research Group, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia;Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia;Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia;Proteomics, Metabolomics and MS-Imaging Core Facility, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia;The University of Adelaide, School of Medicine, North Terrace, Adelaide, SA, Australia;

关键词: Alzheimer’s disease;    Dementia;    Knock-in;    AppNL-G-F/NL-G-F;    Lysosome;    β-hexosaminidase;   

DOI  :  

来源: DOAJ

【 摘 要 】

Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer’s disease (AD), which appear early and are progressive in nature. Sandhoff disease and Tay-Sachs disease (neurological lysosomal storage diseases caused by mutations in genes that code for critical subunits of β-hexosaminidase) result in accumulation of amyloid-β (Aβ) and related proteolytic fragments in the brain. However, experiments that determine whether mutations in genes that code for β-hexosaminidase are risk factors for AD are currently lacking. To determine the relationship between β-hexosaminidase and AD, we investigated whether a heterozygous deletion of Hexb, the gene that encodes the beta subunit of β-hexosaminidase, modifies the behavioural phenotype and appearance of disease lesions in AppNL-G-F/NL-G-F (AppKI/KI) mice. AppKI/KI and Hexb+/- mice were crossed and evaluated in a behavioural test battery. Neuropathological hallmarks of AD and ganglioside levels in the brain were also examined. Heterozygosity of Hexb in AppKI/KI mice reduced learning flexibility during the Reversal Phase of the Morris water maze. Contrary to expectation, heterozygosity of Hexb caused a small but significant decrease in amyloid beta deposition and an increase in the microglial marker IBA1 that was region- and age-specific. Hexb heterozygosity caused detectable changes in the brain and in the behaviour of an AD model mouse, consistent with previous reports that described a biochemical relationship between HEXB and AD. This study reveals that the lysosomal enzyme gene Hexb is not haplosufficient in the mouse AD brain.

【 授权许可】

Unknown