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
Gandal, Michael J; Haney, Jillian R; Parikshak, Neelroop N et al. (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359:693-697
Barnes, Josephine; Bartlett, Jonathan W; Wolk, David A et al. (2018) Disease Course Varies According to Age and Symptom Length in Alzheimer's Disease. J Alzheimers Dis 64:631-642
Schaffert, Jeff; LoBue, Christian; White, Charles L et al. (2018) Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease. Neuropsychology 32:410-416
Huckins, L M; Hatzikotoulas, K; Southam, L et al. (2018) Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. Mol Psychiatry 23:1169-1180
Soleimani, Laili; Ravona-Springer, Ramit; Heymann, Anthony et al. (2018) Depression is more strongly associated with cognition in elderly women than men with type 2 diabetes. Int Psychogeriatr :1-5
Ki?emet-Piska?, Spomenka; Babi? Leko, Mirjana; Blažekovi?, Antonela et al. (2018) Evaluation of cerebrospinal fluid phosphorylated tau231 as a biomarker in the differential diagnosis of Alzheimer's disease and vascular dementia. CNS Neurosci Ther 24:734-740
Audrain, Mickael; Haure-Mirande, Jean-Vianney; Wang, Minghui et al. (2018) Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau. Mol Psychiatry :
Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2018) Decreasing hazards of Alzheimer's disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E. Int J Geriatr Psychiatry 33:200-211
Zhu, Carolyn W; Grossman, Hillel; Neugroschl, Judith et al. (2018) A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer's disease: A pilot study. Alzheimers Dement (N Y) 4:609-616
Boban, Mirta; Babi? Leko, Mirjana; Miški?, Terezija et al. (2018) Human neuroblastoma SH-SY5Y cells treated with okadaic acid express phosphorylated high molecular weight tau-immunoreactive protein species. J Neurosci Methods :

Showing the most recent 10 out of 555 publications