Frontotemporal dementia (FTD), a devastating, rapidly progressive neurodegenerative disease, accounts for 15-20% of all dementia cases and particularly common in patients under 65 years of age. FTD patients suffer progressive neurodegeneration in the frontal lobes and other brain regions, resulting in behavioral changes, and memory and motor neuron deficits. Compared with other age-dependent neurodegenerative diseases, the molecular, cellular, and genetic bases of FTD are poorly understood, although there is increasing recognition of pathological overlap with other neurodegenerative diseases. Genetic causes are estimated to account for ~40% of FTD, and since 1998, dominant mutations in four causative genes have been identified. These include mutations of tau, valosin-containing protein (VCP), CHMP2B, and progranulin. The identification of these genes allows for the generation of sorely needed animal models of FTD. The overall goal of this proposal it to generate murine models for FTD, focusing on progranulin and VCP. Murine models will enable detailed study of the pathogenesis, testing of genetic interactions between contributing mechanisms, and testing of emerging therapies.
Aim 1 is to generate mouse models for FTD caused by progranulin deficiency. Specifically, we will generate mice lacking progranulin in the whole body and, with Cre-LoxP methodology, in neurons and microglia. Additionally, we will generate mice that harbor a disease- specific nonsense mutation (corresponding to the human mutation R493X), which will provide a model for testing therapies that target non-sense mutations.
Aim 2 is to generate transgenic mice expressing human VCP with an FTD mutation (R155H) in neurons. We will also test whether a genetic interaction exists between VCP mutations and Pgrn mutations by crossing the different models. The phenotypes of each of these potential disease models will be extensively analyzed, many aspects with the assistance of expert local collaborators.These.mouse models will enable us to complement on-going cell-based studies of disease pathogenesis with in vivo testing of emerging hypotheses. The mice will also be deposited in public repositories, making them generally available to the research community.

Public Health Relevance

(Seeinstructions): Dementias due to progressive loss of brain function are huge health problems confronting our population. Frontotemporal dementia (FTD), a rapidly progressive and devastating disease, is less well known than Alzheimer's disease but is emerging as a relatively common cause of dementia. Currently, there are no cures and there are no proven animal models. We propose to generate mouse models of FTD, both to study how the disease occurs and to provide a means to test new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG023501-09
Application #
8375371
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2012-04-15
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$194,870
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bonham, Luke W; Geier, Ethan G; Steele, Natasha Z R et al. (2018) Insulin-Like Growth Factor Binding Protein 2 Is Associated With Biomarkers of Alzheimer's Disease Pathology and Shows Differential Expression in Transgenic Mice. Front Neurosci 12:476
Schneider, Raphael; McKeever, Paul; Kim, TaeHyung et al. (2018) Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study. J Neurol Neurosurg Psychiatry 89:851-858
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
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Karch, Celeste M; Wen, Natalie; Fan, Chun C et al. (2018) Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum. JAMA Neurol 75:860-875
Scheltens, Nienke M E; Tijms, Betty M; Heymans, Martijn W et al. (2018) Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression. J Alzheimers Dis 65:1029-1039
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
Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600
Staffaroni, Adam M; Brown, Jesse A; Casaletto, Kaitlin B et al. (2018) The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed. J Neurosci 38:2809-2817
Hanfelt, John J; Peng, Limin; Goldstein, Felicia C et al. (2018) Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center. Neurobiol Dis 117:62-71

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