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

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 beta-hexosaminidase) result in accumulation of amyloid-beta (A beta) and related proteolytic fragments in the brain. However, experiments that determine whether mutations in genes that code for beta-hexosaminidase are risk factors for AD are currently lacking. To determine the relationship between beta-hexosaminidase and AD, we investigated whether a heterozygous deletion of Hexb, the gene that encodes the beta subunit of beta-hexosaminidase, modifies the behavioural phenotype and appearance of disease lesions in App(NL-G-F/NL-G-F) (App(KI/KI)) mice. App(KI/KI) and Hexb(+/-& nbsp;)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 App(KI/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.

Automated summary

Lysosomal network abnormalities are a significant feature of Alzheimer's disease, and reduced expression of the Hexb gene may lead to related pathological changes and behavioral alterations in an AD model mouse.