Alzheimer's disease (AD), the sixth leading cause of death in the United States, currently affects over 5 million North Americans and their families as well as the United States health care system. Impaired olfactory perceptual acuity, including deficits in odor identification, detection and discrimination are often observed early in the progression of AD. Understanding the neural basis for these sensory deficits is important in that 1) their etiology may unveil new insights into AD pathogenesis and 2) olfactory screens may serve as early-indicators of AD when combined with neuropsychological examinations.
SPECIFIC AIMS : This proposal describes an experimental strategy aimed at understanding the contributions of amyloid-2 (A2) to olfactory system dysfunction. Behavioral, neurophysiological and molecular experiments will be performed in mice which overexpress human mutations of Amyloid 2 Precursor Protein (APP).
Aim 1 will test the hypothesis that progressive A2 burden and AD-like olfactory perceptual deficits are related to abnormal odor information processing at local and global levels in AP transgenic mice. The remaining two aims will utilize novel genetic models of A2 remediation to examine methods to rescue/preserve olfactory function in APP transgenics.
AIM 2 wil test the hypothesis that chronic enhancement of A2 degradation improves olfactory processing and perception by using mice which lack the protease inhibitor cystatin B (CBKO).
AIM 3 will use mice over expressing the protease inhibitor cystatin C (CysC) to test the hypothesis that preventing A2 aggregation improves olfactory procesing and perception. These ongoing studies are the first to directly assess the contributions of A2 to olfactory perceptual dysfunction.

Public Health Relevance

Alzheimer's disease (AD) often results in impaired olfactory perceptual function - the cause of which is unknown. The proposed experiments will utilize olfactory behavioral and neurophysiological indicators of olfactory dysfunction in transgenic mice to understand the basis for the pathogenic role of A2 in AD-related perceptual loss. Understanding A2-related sensory loss will provide potential avenues for early diagnosis of AD, a foundation for therapies of sensory loss in AD, and possibly may clarify basic mechanisms underlying AD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037693-02
Application #
8254386
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Chen, Wen G
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$323,900
Indirect Cost
$118,900
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Kimball, Bruce A; Wilson, Donald A; Wesson, Daniel W (2016) Alterations of the volatile metabolome in mouse models of Alzheimer's disease. Sci Rep 6:19495
Mathews, Paul M; Levy, Efrat (2016) Cystatin C in aging and in Alzheimer's disease. Ageing Res Rev 32:38-50
Albers, Mark W; Gilmore, Grover C; Kaye, Jeffrey et al. (2015) At the interface of sensory and motor dysfunctions and Alzheimer's disease. Alzheimers Dement 11:70-98
Xu, Wenjin; Fitzgerald, Shane; Nixon, Ralph A et al. (2015) Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AβPP metabolites in the Tg2576 mouse model of Alzheimer's disease. Exp Neurol 264:82-91
Xu, Wenjin; Lopez-Guzman, Mirielle; Schoen, Chelsea et al. (2014) Spared piriform cortical single-unit odor processing and odor discrimination in the Tg2576 mouse model of Alzheimer's disease. PLoS One 9:e106431
Barnes, Dylan C; Wilson, Donald A (2014) Sleep and olfactory cortical plasticity. Front Behav Neurosci 8:134
Wilson, Donald A; Xu, Wenjin; Sadrian, Benjamin et al. (2014) Cortical odor processing in health and disease. Prog Brain Res 208:275-305
Kaur, Gurjinder; Sharma, Ajay; Xu, Wenjin et al. (2014) Glutamatergic transmission aberration: a major cause of behavioral deficits in a murine model of Down's syndrome. J Neurosci 34:5099-106
Wesson, Daniel W; Morales-Corraliza, Jose; Mazzella, Matthew J et al. (2013) Chronic anti-murine Aýý immunization preserves odor guided behaviors in an Alzheimer's ýý-amyloidosis model. Behav Brain Res 237:96-102
Morales-Corraliza, Jose; Schmidt, Stephen D; Mazzella, Matthew J et al. (2013) Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model. Neurobiol Aging 34:137-45

Showing the most recent 10 out of 24 publications