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 App NL-G-F/NL-G-F (App KI/KI ) mice. App KI/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 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.