Aging is the single most important risk factor for Alzheimer's disease (AD), which represents the most common cause of dementia in the world. Our group has shown that a naturally occurring switch from the TrkA to the p75 neurotrophin receptor system is responsible for the activation of amyloid p-peptide (A[3) that characterizes aging. Such an event occurs downstream of the aging program mediated by the insulin-like growth factor 1 receptor (IGF1-R), and leads to activation of neutral sphingomyelinase (nSMase), the enzyme that generates the lipid second messenger ceramide. Ceramide, in turn, is responsible for the molecular stabilization of BACE1 and the increased production of Ap. The above events can be blocked by genetic and biochemical approaches that target IGF1-R, p75NTR, or nSMase. In the Preliminary Studies Section, we report that ceramide regulates a transient form of lysine acetylation of nascent BACE1 that affects the molecular stability of the p secretase. This process involves lysine acetylation in the lumen of the ER/ERGIC and is followed by deacetylation in the lumen of the Golgi apparatus, once the nascent protein is fully mature. Given the role that BACE1 plays in the molecular pathogenesis of AD, our results have profound implications for the neurobiology of the disease. The central hypothesis of this proposal is that ceramide is the last output of a signaling pathway that controls AD-neuropatholoqy during aging. Specifically, we propose that ceramide regulates AB generation by affecting the acetylation and molecular stability of BACE1, the rate-limiting enzyme for the biogenesis of Ap.
Specific Aim 1 will study the biochemical properties of the acetyl-CoA membrane transporter, which translocates acetylCoA from the cytosol to the lumen of the ER, where it serves as donor of acetyl groups for the molecular stabilization of BACE1.
Specific Aim 2 will study the function and biochemical properties of two newly-identified acetylCoA:lysine acetyltransferases that are required for the molecular stabilization of BACE1, downstream of ceramide. For the execution of the above two Specific Aims, we have described a combination of biochemical and genetic approaches. The biochemical approaches include enzymatic assays, in vitro reconstitution, affinity purification, subcellular fractionation studies, and depletion studies. The genetic approaches include stable transfection and """"""""gene-silencing"""""""" of the above targets. Finally, translational research is described as part of our proposal to translate our findings into novel therapeutic approaches to prevent late-onset AD.

Public Health Relevance

Aging is the single most important risk factor for Alzheimer's disease (AD). Because of the increase in life expectancy that we are experiencing, AD is predicted to affect 45 million individuals worldwide by the year 2050. We have identified a novel molecular pathway that links aging to AD neuropathology. The long-term objective of this proposal is to characterize this pathway and design new approaches for the prevention of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG033514-05
Application #
8449655
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$121,244
Indirect Cost
$38,841
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Dempsey, Robert J; Jackson, Daren C; Wilbrand, Stephanie M et al. (2018) The Preservation of Cognition 1 Year After Carotid Endarterectomy in Patients With Prior Cognitive Decline. Neurosurgery 82:322-328
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
Gallagher, Damien; Kiss, Alex; Lanctot, Krista L et al. (2018) Toward Prevention of Mild Cognitive Impairment in Older Adults With Depression: An Observational Study of Potentially Modifiable Risk Factors. J Clin Psychiatry 80:
Cummings, Nicole E; Williams, Elizabeth M; Kasza, Ildiko et al. (2018) Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol 596:623-645
Christensen, Krista; Gleason, Carey E; Mares, Julie A (2018) Dietary carotenoids and cognitive function among US adults, NHANES 2011-2014. Nutr Neurosci :1-9
Westmark, Cara J (2018) Fragile X and APP: a Decade in Review, a Vision for the Future. Mol Neurobiol :
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
Davis, Jeremy J (2018) Performance validity in older adults: Observed versus predicted false positive rates in relation to number of tests administered. J Clin Exp Neuropsychol 40:1013-1021
Barzgari, Amy; Sojkova, Jitka; Maritza Dowling, N et al. (2018) Arterial spin labeling reveals relationships between resting cerebral perfusion and motor learning in Parkinson's disease. Brain Imaging Behav :
Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27

Showing the most recent 10 out of 374 publications