Amyloidopathy is an important feature of several dementias - Alzheimer disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson disease dementia (PDD). Amyloid (Ab) peptide production is an important therapeutic target. Experimental in vitro and murine genetic model experiments indicate that Ab peptide production is reduced by activation of some G-protein coupled receptors, including serotonin receptors. Modest human data supports these interesting observations. Based on preliminary studies, our central hypothesis is that serotoninergic neurotransmission inhibits Ab amyloid production-deposition. An important corollary of this hypothesis is that diminished regional serotoninergic innervation should correlate inversely with Ab deposition. Parkinson disease (PD) - a disorder characterized by variable degeneration of serotoninergic projection systems and variable Ab peptide deposition - provides a model to evaluate this corollary prediction. In preliminary PET imaging studies of PD subjects, we found a strong inverse correlation between regional forebrain serotoninergic innervation and Ab deposition as measured with the serotonin transporter ligand [11C]DASB and the amyloid ligand [11C]PiB, respectively. These intriguing data are limited by relatively small sample size and cross-sectional study design. We propose a larger longitudinal study of PD subjects that will yield more specific assessments of the interactions between serotoninergic system changes and brain Ab amyloid deposition. To determine if the relationship between regional serotoninergic innervation and Ab amyloid deposition is generalizable, we will perform a parallel cross-sectional study in a sample of cognitively asymptomatic elderly controls. Validation of our predictions will strongly support the implementation of clinical investigations in PD and other pre-dementias aimed at using serotoninergic agents to modify the natural history of cerebral Ab peptide production-deposition. Falsification of our predictions will be equally valuable as it would undermine the central hypothesis and forestall the implementation of clinical trials of serotoninergic agents as disease modifying agents in MCI, AD, DLB, and PD.

Public Health Relevance

Production of the abnormal protein Ab amyloid is a central feature of several dementias. Prior experimental animal work suggests that Ab amyloid production can be decreased by the neurotransmitter serotonin. We will test this idea in Parkinson disease (PD) subjects using positron emission tomography imaging of brain serotonin containing brain cells and correlate loss of these brain cells with brain Ab amyloid load. This work may suggest new treatment approaches for dementias.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56NS082941-01A1
Application #
8928719
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sutherland, Margaret L
Project Start
2014-09-28
Project End
2015-08-31
Budget Start
2014-09-28
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$680,124
Indirect Cost
$242,393
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109