Basic Science and Pathogenesis

Although lysosome dysfunction has been implicated in Alzheimer's disease (AD), it is unclear what level or type of dysfunction is pathogenic. We hypothesize that haploinsufficiency of lysosomal enzymes is associated with AD and that CNS-directed, AAV-mediated gene transfer can be an effective treatment.

Although lysosome dysfunction has been implicated in Alzheimer's disease (AD), it is unclear what level or type of dysfunction is pathogenic. We hypothesize that haploinsufficiency of lysosomal enzymes is associated with AD and that CNS-directed, AAV-mediated gene transfer can be an effective treatment.

Heterozygous protein-damaging mutations in several lysosomal enzyme genes are enriched in AD patients compared to matched controls. Proteomic analysis shows that the lysosomal storage disease pathway is activated in the brains of AD patients. There is a gene-dosage effect on Ab₄₀ levels in brain ISF between WT, heterozygous, and homozygous PPT1 deficient mice. Although APP is not changed, the levels of a-, b-, and g-secretases are altered in PPT1 heterozygous mice in a pattern that favors an amyloidogenic pathway. Heterozygosity of PPT1 increases Ab plaques, insoluble Ab40 and Ab42 levels, and decreases the life span of 5xFAD mice. Consistent with the human genetic and murine data, the AD pathway is activated in heterozygous PPT1 sheep. AAV-mediated gene therapy in 5xFAD/PPT1+/- mice decreased the Ab burden, increased life span, and improved cognitive function. The effects of heterozygosity of the NAGLU, GALC, IDUA, and GUSB genes on Ab pathology were nearly identical to those observed for PPT1 heterozygosity.

These data strongly implicate heterozygosity of at least five, likely more, lysosomal enzyme genes in the development of AD and these genes might be effective therapeutic targets in certain genetically-defined forms of AD.