Neuropathology in cognitively impaired elderly individuals is commonly multifactorial, including Alzheimer type pathology, ischemic/vascular lesions, Lewy bodies, hippocampal sclerosis and TDP-43 proteinopathy. Recently, the latter two have shown to be linked. TDP-43 is the major protein that accumulates in neuronal inclusions in frontotemporal degeneration with ubiquitinated inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS), but it is also detected in other disorders that show no obvious relationship to FTLD-U or ALS, suggesting alternative mechanisms for TDP-43 pathology. Mutations in the gene for progranulin {GRH) cause FTLD-U with hippocampal sclerosis, and almost all mutations are mediated by decreases in progranulin expression. The undeniable fact from these observations is that even partial decreases in progranulin over time lead to severe neurologic consequences. In cell culture studies, decreases in progranulin induce apoptosis, caspase-mediated TDP-43 cleavage and TDP-43 inclusions. Common variants in miRNA binding sites in the 3'UTR of GRN have been shown to increase the risk of FTLD-U through decreased progranulin expression;the same genetic variants predispose to hippocampal sclerosis. The goals of this proposal are to investigate these phenomena and there relationship to glucocorticoid mediated stress. The underlying hypothesis is that decreased progranulin expression, due to genetic or environmental factors or both, predisposes to neurodegeneration, particularly in the hippocampus. We hypothesize that deficiencies in progranulin predispose to hippocampal sclerosis. To address this hypothesis, studies are proposed in human autopsy tissue and in a mouse model of progranulin deficiency. In humans we will determine GR/V genotype and levels of progranulin in brains of individuals with and without hippocampal sclerosis. We hypothesize that hippocampal sclerosis will be associated with programed cell death that leads to TDP-43 pathology. To this end we will study TDP-43 pathology in hippocampal sclerosis with respect to markers of programmed cell death, as well as other possible stressors such as hypoxia, microvascular pathology and glucocorticoid stress. The animal studies will subject progranulin knockout mice and controls to glucocorticoid-mediated stress (physical restraint) to see if hippocampal pathology is greater in progranulin deficient animals. Similar experiments will be conducted in progranulin knock-out mice that have been crossbred with TDP-43 transgenic mice.

Public Health Relevance

Project 4 aims to determine the interplay between common genetic variants in the progranulin gene and risk for hippocampal pathology in response to stress. The findings have relevance for understanding risk factors (particularly stress) for hippocampal neuronal loss and its amnestic syndrome, which are common problems in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG003949-28
Application #
8447456
Study Section
Special Emphasis Panel (ZAG1-ZIJ-1)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
28
Fiscal Year
2013
Total Cost
$177,610
Indirect Cost
$76,014
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Blumen, Helena M; Brown, Lucy L; Habeck, Christian et al. (2018) Gray matter volume covariance patterns associated with gait speed in older adults: a multi-cohort MRI study. Brain Imaging Behav :
Kidana, Kiwami; Tatebe, Takuya; Ito, Kaori et al. (2018) Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice. EMBO Mol Med 10:
Sanchez-Contreras, Monica Y; Kouri, Naomi; Cook, Casey N et al. (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener 13:37
Kasanuki, Koji; Ross, Owen A; DeTure, Michael A et al. (2018) Relationships between lewy and tau pathologies in 375 consecutive non-Alzheimer's olfactory bulbs. Mov Disord 33:333-334
Ogaki, Kotaro; Martens, Yuka A; Heckman, Michael G et al. (2018) Multiple system atrophy and apolipoprotein E. Mov Disord 33:647-650
Hyun, Jinshil; Sliwinski, Martin J; Almeida, David M et al. (2018) The moderating effects of aging and cognitive abilities on the association between work stress and negative affect. Aging Ment Health 22:611-618
Fleysher, Roman; Lipton, Michael L; Noskin, Olga et al. (2018) White matter structural integrity and transcranial Doppler blood flow pulsatility in normal aging. Magn Reson Imaging 47:97-102
Sliwinski, Martin J; Mogle, Jacqueline A; Hyun, Jinshil et al. (2018) Reliability and Validity of Ambulatory Cognitive Assessments. Assessment 25:14-30
Zammit, Andrea R; Robitaille, Annie; Piccinin, Andrea et al. (2018) Associations between aging-related changes in grip strength and cognitive function in older adults: A systematic review. J Gerontol A Biol Sci Med Sci :
Graham-Engeland, Jennifer E; Sin, Nancy L; Smyth, Joshua M et al. (2018) Negative and positive affect as predictors of inflammation: Timing matters. Brain Behav Immun 74:222-230

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