Comparative DNA Sequence Variation in Alzheimer Genes

The combination of phylogenetic proximity to humans and high levels of intraspecific genetic variation has already allowed successful identification of DNA sequence variation in Alzheimer Disease (AD)- related genes in chimpanzees during Phase 1. This Phase 2 proposal will develop. SNP genotyping capabilities for those polymorphisms and genotype pre-existing chimpanzee brain tissues and aged living chimpanzees. An ACT assay will be used to identify chimpanzees with probable dementia and demarcate phenotypes for a disease-oriented sequencing strategy in a small panel of chimpanzee DNA samples. We will identify variation at another five candidate genes thought to contain AD-related mutations in humans (A2M, tau, LPL, LRP2 and mtDNA). Characterization of polymorphisms will broaden our phylogenetic understanding of important human disease genes, help develop improved genotyping methods for single nucleotide polymorphisms (SNPs), advance investigation of gene/disease associations in AD and facilitate pharmacogenetic approaches to identifying potential AD- related pharmaceuticals. The genetic characterization of chimpanzee brain tissues will increase the value of our Great Ape Brain Bank. The study of a host of AD-related genes that seem to be involved in Ab formation and clearance can allow correlation of neuropathological studies with AD-related mutations for a phylogenetically informed understanding of the genetic basis of AD. PROPOSED COMMERCIAL APPLICATIONS: This project will increase the scientific and commercial value of BIOQUAL's Great Ape Brain Bank by providing genotypic data on Alzheimer-related genes on the brain tissues in that collection. Further commercial value is gained by advancing our understanding of the relationship between AD-related genes, cognitive impairment, and neuropathology in a chimpanzee model of human neurodegenerative disease. Chimpanzees and chimpanzee brain tissues that have been characterized for AD-related genetic polymorphisms can be useful for post-mortem assessment of neuropathology related to AD or other neurodegenerative disorders. Living animals could potentially be treated with candidate pharmaceutical agents for their own welfare and translated into humans. Overall, this knowledge can help alleviate human suffering encountered by a growing fraction of the U.S. population and reduce the public health burden associated with AD and related neurodegenerative disorders in an aging population.