The hypothesis driving the current proposal is that multiple y-secretase substrates are misprocessed in mutant presenilin 1 familial Alzheimer's disease (PS1 FAD) and that a multisubstrate misprocessing """"""""signature"""""""" is also similarly associated with sporadic AD. To this end, we have recently demonstrated that """"""""APP p3-like"""""""" alcadein peptides (p3-Alcs) are generated by typical a- and y-secretases, and p3-Alc C termini are modulated by FAD mutant PS1. In neurons. Ale proteins form complexes with X11L molecules, which, in turn, complex with APP. For this reason, we chose Ale proteins as representative y-secretase substrates that might undergo misprocessing in AD in parallel with APP. Plotting minor/major p3-Alc variant ratios (analogous to AB42/40 ratios) against the corresponding AB42/40 ratios in media conditioned by a panel of FAD-mutant PSI-expressing cells reveals a highly linear covariant relationship between p3-Alc ratios and AB42/40 ratios. We interpret the disease-related change in regression slope as a signature for y secretase dysfunction. p3-Alcs were also detected in human cerebrospinal fluid (CSF), and, again, a covariant signature was associated with the AD phenotype. The association of the sporadic AD phenotype with a distinct p3-Alc:Ap covariant ratio signature provides evidence that y-secretase dysfunction may contribute to the pathogenesis of sporadic AD. Thus, our Specific Aims are: 1) To characterize Ale metabolites in regions of the cerebral cortex of elderly non-demented humans and patients with differential degrees of dementia;2) To characterize the distribution of Ales in the cerebral cortex of elderly nondemented humans and patients with differential degrees of dementia;and 3) To characterize the cortical and synaptic distribution of Ales in relevant mouse models of AD and analyze their relationship with the progression of neuronal alterations. The information from human brain and from the brains of mouse models should guide us in future efforts to understand the AB:Alc metabolic covariance as well as the possible implications of AB:Alc metabolic covariance for the pathogenesis and diagnosis of sporadic AD.

Public Health Relevance

The most common genetic form of Alzheimer's is due to dysfunction of the enzyme gamma secretase. We developed a new spinal fluid test to determine whether gamma secretase might function improperly in common forms of Alzheimer's. We now propose to look at what goes on inside the brain to cause the spinal fluid changes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG005138-26
Application #
8014553
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J2))
Project Start
Project End
Budget Start
2010-05-01
Budget End
2011-03-31
Support Year
26
Fiscal Year
2010
Total Cost
$254,076
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600
Mincer, Joshua S; Baxter, Mark G; McCormick, Patrick J et al. (2018) Delineating the Trajectory of Cognitive Recovery From General Anesthesia in Older Adults: Design and Rationale of the TORIE (Trajectory of Recovery in the Elderly) Project. Anesth Analg 126:1675-1683
Hanfelt, John J; Peng, Limin; Goldstein, Felicia C et al. (2018) Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center. Neurobiol Dis 117:62-71
Ting, Simon Kang Seng; Foo, Heidi; Chia, Pei Shi et al. (2018) Dyslexic Characteristics of Chinese-Speaking Semantic Variant of Primary Progressive Aphasia. J Neuropsychiatry Clin Neurosci 30:31-37
Bryois, Julien; Garrett, Melanie E; Song, Lingyun et al. (2018) Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat Commun 9:3121
Miller, M L; Ren, Y; Szutorisz, H et al. (2018) Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23:1328-1335
Fazio, Leonardo; Pergola, Giulio; Papalino, Marco et al. (2018) Transcriptomic context of DRD1 is associated with prefrontal activity and behavior during working memory. Proc Natl Acad Sci U S A 115:5582-5587
Gusev, Alexander; Mancuso, Nicholas; Won, Hyejung et al. (2018) Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet 50:538-548
Burke, Shanna L; Hu, Tianyan; Fava, Nicole M et al. (2018) Sex differences in the development of mild cognitive impairment and probable Alzheimer's disease as predicted by hippocampal volume or white matter hyperintensities. J Women Aging :1-25
Khan, Atlas; Liu, Qian; Wang, Kai (2018) iMEGES: integrated mental-disorder GEnome score by deep neural network for prioritizing the susceptibility genes for mental disorders in personal genomes. BMC Bioinformatics 19:501

Showing the most recent 10 out of 555 publications