The neuronal adaptor protein X11alpha/mint-1 interacts with amyloid precursor protein (APP) to regulate its trafficking and processing in vitro. In transfected non-neuronal cells, X11alpha inhibits alpha- and gamma- but not beta- cleavage of APP. Because the phosphotyrosine binding (PTB) domain of X11alpha interacts specifically with the APP family, X11alpha appears to inhibit gamma-cleavage of APP specifically while sparing gamma-cleavage of Notch and other substrates of regulated intramembranous proteolysis. To determine the in vivo significance of these in vitro data, we will generate and characterize novel hX11alpha transgenic mice and X11alpha knockout mice and examine murine APP metabolism. Crosses of these mice to Tg2576 mice (transgenic for the Swedish mutation of hAPP, or hAPPswe) will probe the effects of XI la on hAPPswe metabolism and on the development of partial AD-like phenotypes in aging brain. A recent human genome-wide analysis revealed significant linkage of sporadic AD to single nucleotide polymorphisms (SNPs) on chromosome 9, perhaps including the X11alpha region. We will probe genetic linkage of SNPs in the X11alpha region to sporadic AD by using genomic DNA extracted from samples from AD subjects versus carefully-matched control subjects.
The specific aims are to: 1) generate X11alpha knockout and hX11alpha transgenic mice and determine effects on murine APP metabolism in brain and in primary neuronal cultures, 2) cross X11alpha knockout and hX11alpha transgenic mice with Tg2576 mice to determine a) modulatory effects on hAPPswe metabolism in brain and in neuronal cultures, and b) development of AD-like phenotypes with aging, and 3) elucidate the SNPs and haplotypes within or adjacent to the X11alpha gene of AD cases and age-, gender-, and ApoE-matched controls to determine if there is a statistically significant link to sporadic AD.
Specific aim 3 will study DNA samples obtained from the Pathology Core and from other ADRCs. These results will 1) inform the normal functions of X11alpha as well as APP and its derivatives in CNS neurons, 2) lay the groundwork for viral-vector based gene therapy of AD using either X11alpha or its PTB domain in hAPP transgenic mouse models, and 3) probe a potential genetic risk factor of sporadic AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG008671-20
Application #
7870455
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
20
Fiscal Year
2009
Total Cost
$234,278
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Michaud, Tzeyu L; High, Robin; Charlton, Mary E et al. (2017) Dependence Stage and Pharmacoeconomic Outcomes in Patients With Alzheimer Disease. Alzheimer Dis Assoc Disord 31:209-217
Monin, Joan K; Poulin, Michael J; Brown, Stephanie L et al. (2017) Spouses' daily feelings of appreciation and self-reported well-being. Health Psychol 36:1135-1139
Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738
Cary, Brian P; Brooks, Allen F; Fawaz, Maria V et al. (2016) Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts. ACS Chem Neurosci 7:391-8
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-121
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-200.e20
Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-150
Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108-17

Showing the most recent 10 out of 274 publications