Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia after Alzheimer's disease (AD) in patients <65 years of age. Tau and TDP-43 pathology variants of FTLD (FTLD-Tau and FTLD-TDP, respectively) account for -90 of FTLD cases, but TDP-43 pathology occurs in >50% of patients with AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Guam amyotrophic lateral sclerosis (ALS)/Parkinson Dementia Complex (ALS/PDC). Despite the fact that this neuropathology overlap is well known, it is unclear how comorbid Ap, tau and alpha-synuclein pathology modify TDP-43 mediated neurodegeneration in patients with frontotemporal dementia (FTD). Conversely, it is unknown how TDP-43 modifies Ap, tau and alpha-synuclein pathologies, but TDP-43 pathology is known to independently contribute to behavioral impairments in AD. Since these issues are tractable to investigate experimentally in transgenic (Tg) mouse models of TDP-43, tau, Ap and alpha-synuclein pathology. Project 4 tests the hypothesis that comorbid tau, Ap and alpha-synuclein pathologies in Tg mice independently modify TDP-43 mediated neurodegeneration and wee versa. This will be done by studying TDP-43 Tg mice which recapitulate the hallmark features of FTLD-TDP that we cross with our previously characterized mutant P301S tau Tg mice which show tau mediated neurodegeneration, behavioral impairments and premature death, Tg2576 Tg mice that model AD-like Ap pathology and our extensively studied M83 alpha-synuclien Tg mice that develop Lewy body pathology, motor impairments and lethal neurodegeneration. Implementing these Aims will elucidate how TDP-43 mediated neurodegenerative disease is modified by comorbid tau, Ap and alpha-synuclien pathologies and vice versa. These studies are highly significant because they will clarify mechanisms of TDP-43 proteinopathy and they have translational potential to improve both the diagnosis and the treatment of patients with TDP-43 proteinopathy.

Public Health Relevance

Project 4 tests the hypothesis that frontotemporal dementia (FTD) patients with co-incident Alzheimer's disease (AD) pathology (tau tangles, Ap plaques), or Parkinson's disease (PD) pathology (alpha-synuclein Lewy bodies) may have a different disease course and responses to therapies than those without these comorbid pathologies and vice versa. Although tau, Ap and alphasynuclein lesions often co-occur with TDP-43 pathologies in the same patient, these issues are difficult to address in patients but they are readily addressed in studies of transgenic (Tg) mouse models of TDP-43 mediated neurodegeneration that are/are not crossed with Tg mouse models of AD or PD pathologies. Thus, the relevance of Project 4 to human health is that it will elucidate how TDP-43 mediated neurodegeneration is modified by comorbid tau, Ap and alpha-synuclien pathologies and vice versa. These studies are highly significant because they will clarify mechanisms of TDP-43 proteinopathy and have translational potential to improve the diagnosis and treatment of patients with FTD, AD, PD and related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017586-12
Application #
8377716
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$300,920
Indirect Cost
$112,845
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Spinelli, Edoardo G; Mandelli, Maria Luisa; Miller, Zachary A et al. (2017) Typical and atypical pathology in primary progressive aphasia variants. Ann Neurol 81:430-443
Berson, Amit; Sartoris, Ashley; Nativio, Raffaella et al. (2017) TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol 27:3579-3590.e6
Nevler, Naomi; Ash, Sharon; Jester, Charles et al. (2017) Automatic measurement of prosody in behavioral variant FTD. Neurology 89:650-656
Cousins, Katheryn A Q; Ash, Sharon; Irwin, David J et al. (2017) Dissociable substrates underlie the production of abstract and concrete nouns. Brain Lang 165:45-54
Zylstra, Bradley; Netscher, George; Jacquemot, Julien et al. (2017) Extended, continuous measures of functional status in community dwelling persons with Alzheimer's and related dementia: Infrastructure, performance, tradeoffs, preliminary data, and promise. J Neurosci Methods :
Phillips, Jeffrey S; Da Re, Fulvio; Dratch, Laynie et al. (2017) Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease. Neurobiol Aging 63:75-87
Dong, Aoyan; Toledo, Jon B; Honnorat, Nicolas et al. (2017) Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers. Brain 140:735-747
Lee, Edward B; Porta, Sílvia; Michael Baer, G et al. (2017) Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134:65-78
Ballatore, Carlo; Brunden, Kurt R; Trojanowski, John Q et al. (2017) Non-Naturally Occurring Small Molecule Microtubule-Stabilizing Agents: A Potential Tactic for CNS-Directed Therapies. ACS Chem Neurosci 8:5-7
Kim, Benjamin J; Irwin, David J; Song, Delu et al. (2017) Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration. Neurology 89:1604-1611

Showing the most recent 10 out of 549 publications