Oral Presentation International Congress on Neuronal Ceroid Lipofuscinoses 2025

Heterozygosity of lysosomal enzyme genes and Alzheimer’s disease (132011)

Mark Sands 1 , Bruno A Benitez 2 3 , Clare E Wallace 4 , Maulikkumar Patel 5 , Carla M Yuede 5 , Samantha L Eaton 6 , Hannah M Edwards 4 , Brookelyn M Doherty 4 , Ryan T Harrigan 4 , Dominic Kurian 6 , Thomas M Wishart 6 , Colin Smith 7 , Neal Goodwin 8 , John R Cirrito 4
  1. Washington University School of Medicine, Elberton, GEORGIA, United States
  2. Departments of Medicine, Washington University
  3. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
  4. Neurology, Washington University
  5. Psychiatry, Washington University
  6. Roslin Institute, , University of Edinburgh
  7. Center for Clinical Brain Sciences, University of Edinburgh
  8. Jaya Biosciences Inc, San Francisco

Although lysosome dysfunction has been implicated in Alzheimer’s disease (AD), it is unclear what level or type of dysfunction is pathogenic.  Heterozygous pathogenic mutations and predicted deleterious variants in several lysosomal enzyme genes, including palmitoyl protein thioesterase-1 (PPT1), are enriched in whole genome sequences from AD patients and matched controls.  Consistent with the human genetic data, proteomic analysis showed that the lysosomal storage disease pathway was activated in brain tissue from AD patients.  There is a gene-dosage effect on Ab40 levels in brain ISF between WT, PPT1 heterozygous, and PPT1 homozygous deficient mice.  Although APP is not changed, the levels of a-, b-, and g-secretases are altered in 18-month-old 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.  Proteomic analysis of the brains of PPT1 heterozygous sheep show that the AD pathway is activated.  AAV-mediated gene therapy in 5xFAD/PPT1+/- mice decreased the Ab burden, increased life span, and improved cognitive function.  We believe that the association between heterozygous mutations in lysosomal enzyme genes and AD extends beyond PPT1.  Similar to PPT1, we showed that heterozygous LoF mutations in the N-acetylglucosaminidase (NAGLU), galactocerebrosidase (GALC), a-L-iduronidase (IDUA), and b-glucuronidase (GUSB) genes affect the levels of Ab40 in brain interstitial fluid (ISF) and increase both the Ab plaque load and levels of insoluble Ab40 and Ab42 in 5xFAD mice.  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.