Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Lysosome dysfunction is implicated in Alzheimer's disease (AD), but the specific pathogenic mechanisms remain unclear.
• This study investigates the role of lysosomal enzyme gene haploinsufficiency in AD pathogenesis.
• The potential of adeno-associated virus (AAV)-mediated gene transfer for treating AD is explored.

Purpose of the Study:

• To determine if haploinsufficiency of lysosomal enzymes is associated with Alzheimer's disease.
• To investigate the therapeutic potential of CNS-directed AAV-mediated gene transfer for AD.
• To explore the impact of specific lysosomal enzyme gene heterozygosity on amyloid pathology.

Main Methods:

• Genetic analysis of lysosomal enzyme genes in AD patients.
• Proteomic analysis of brain tissue to identify activated pathways.
• Murine models (PPT1 deficient and 5xFAD mice) to study gene dosage effects on amyloid-beta (Aβ) pathology.
• AAV-mediated gene therapy in mouse models of AD.

Main Results:

• Heterozygous mutations in lysosomal enzyme genes are enriched in AD patients.
• The lysosomal storage disease pathway is activated in AD brains.
• PPT1 heterozygosity in mice alters secretase activity, increases Aβ plaques and burden, and reduces lifespan.
• AAV gene therapy in 5xFAD/PPT1+/- mice reduced Aβ burden, extended lifespan, and improved cognition.
• Similar effects on Aβ pathology were observed for heterozygosity of NAGLU, GALC, IDUA, and GUSB genes.

Conclusions:

• Heterozygosity of at least five lysosomal enzyme genes is strongly implicated in AD development.
• These lysosomal enzyme genes represent potential therapeutic targets for genetically defined forms of AD.