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

Lauren S. Whyte, Célia Fourrier, Sofia Hassiotis, Adeline A. Lau, Paul J. Trim, Leanne K. Hein, Kathryn J. Hattersley, Julien Bensalem, John J. Hopwood, Kim M. Hemsley, Timothy J. Sargeant

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Abstract

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.

Original languageEnglish
Pages (from-to)131-141
Number of pages11
JournalIBRO Neuroscience Reports
Volume12
DOIs
Publication statusPublished - Jun 2022
Externally publishedYes

Keywords

  • Alzheimer's disease
  • App
  • Dementia
  • Hexb
  • Knock-in
  • Lysosome
  • β-hexosaminidase

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