Lysosomal gene Hexb displays haploinsufficiency in a knock-in mouse model of Alzheimer's disease.
IBRO Neurosci Rep
; 12: 131-141, 2022 Jun.
Article
in En
| MEDLINE
| ID: mdl-35146484
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 ß-hexosaminidase) result in accumulation of amyloid-ß (Aß) and related proteolytic fragments in the brain. However, experiments that determine whether mutations in genes that code for ß-hexosaminidase are risk factors for AD are currently lacking. To determine the relationship between ß-hexosaminidase and AD, we investigated whether a heterozygous deletion of Hexb, the gene that encodes the beta subunit of ß-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.
AD, Alzheimer's disease; APP, amyloid precursor protein; Alzheimer's disease; AppNL-G-F/NL-G-F; Aß, amyloid beta; CD68, cluster of differentiation 68; Dementia; ELISA, enzyme-linked immunosorbent assay; GFAP, glial fibrillary acidic protein; HEXB, ß-hexosaminidase ß subunit; Hexb; IBA1, ionised calcium binding adaptor molecule 1; IL, interleukin; Knock-in; LAMP1, lysosome associated membrane protein 1; LSDs, lysosomal storage disorders; Lysosome; PBS, phosphate buffered saline; TREM2, triggering receptor expressed on myeloid cells 2; ß-hexosaminidase
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
/
Risk_factors_studies
Language:
En
Journal:
IBRO Neurosci Rep
Year:
2022
Document type:
Article
Affiliation country: