SBIR-STTR Award

The goal of this proposal is to identify and characterize DNA sequence variation in chimpanzees at coding regions of four genes that contain mutations implicated in the pathogenesis of Alzheimer Disease (AD). We will select a genetically diverse sample from the four recognized chimpanzee subspecies and characterize DNA sequence variation by screening for novel DNA sequences in 4 candidate genes implicated in AD: Apolipoprotein E, Amyloid Precursor Protein, and Presenilins 1 and 2. Chimpanzees are very similar to humans genetically and physiologically, yet they exhibit substantial intraspecific genetic and phenotypic differentiation. This combination of phylogenetic proximity to humans and intraspecific genetic variation can allow identification of DNA sequence variation in AD-related genes, advance investigation of gene/disease associations in AD, and help identify cost-effective methods of mutation screening. Furthermore, by genetically characterizing brain tissues from chimpanzees that have been behaviorally characterized and made available to neuroscientists, this project can increase the value of our on-going Great Ape Brain Bank initiative. The correlation of neuropathological studies with AD-related mutations can allow detailed investigation of the genetic basis of AD and other neurodegenerative diseases and facilitate a pharmacogenomics approach to testing novel pharmaceuticals in neurogenetically defined chimpanzees prior to human trials. PROPOSED COMMERCIAL APPLICATIONS: This project has commercial value in that it can advance our understanding of the relationship between AD-related genes and neuropathology in chimpanzees. The characterization of neurogenetic loci in chimpanzees can be useful in pharmacogenetic studies of new drugs. This knowledge can help alleviate human suffering and reduce the public health burden associated with AD and related neurodegenerative disorders, which are growing threats to an aging society.

Thesaurus Terms:
Alzheimer's disease, gene expression, gene mutation, neurogenetics, nucleic acid sequence amyloid protein, apolipoprotein E, molecular pathology, presenilin Pan, polymerase chain reaction, single strand conformation polymorphism

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.

Thesaurus Terms:
Alzheimer's disease, biochemical evolution, gene expression, genetic polymorphism, neurogenetics, nucleic acid sequence amyloid protein, apolipoprotein E, molecular pathology, pharmacogenetics, presenilin, species difference Pan, polymerase chain reaction, single strand conformation polymorphism