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.
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.
|Price, Amy Rose; Peelle, Jonathan E; Bonner, Michael F et al. (2016) Causal Evidence for a Mechanism of Semantic Integration in the Angular Gyrus as Revealed by High-Definition Transcranial Direct Current Stimulation. J Neurosci 36:3829-38|
|Makani, Vishruti; Zhang, Bin; Han, Heeoon et al. (2016) Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy. Acta Neuropathol Commun 4:106|
|Ash, Sharon; Ternes, Kylie; Bisbing, Teagan et al. (2016) Dissociation of quantifiers and object nouns in speech in focal neurodegenerative disease. Neuropsychologia 89:141-52|
|Santos-Santos, Miguel A; Mandelli, Maria Luisa; Binney, Richard J et al. (2016) Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration. JAMA Neurol 73:733-42|
|Cousins, Katheryn A Q; Ash, Sharon; Irwin, David J et al. (2016) Dissociable substrates underlie the production of abstract and concrete nouns. Brain Lang 165:45-54|
|Kovalevich, Jane; Cornec, Anne-Sophie; Yao, Yuemang et al. (2016) Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer's Disease and Related Tauopathies. J Pharmacol Exp Ther 357:432-50|
|Vu, An T; Phillips, Jeffrey S; Kay, Kendrick et al. (2016) Using precise word timing information improves decoding accuracy in a multiband-accelerated multimodal reading experiment. Cogn Neuropsychol 33:265-75|
|Shinagawa, Shunichiro; Catindig, Joseree Ann; Block, Nikolas R et al. (2016) When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians. Dement Geriatr Cogn Disord 41:99-108|
|Spiller, Krista J; Restrepo, Clark R; Khan, Tahiyana et al. (2016) Progression of motor neuron disease is accelerated and the ability to recover is compromised with advanced age in rNLS8 mice. Acta Neuropathol Commun 4:105|
|McMillan, Corey T; Irwin, David J; Nasrallah, Ilya et al. (2016) Multimodal evaluation demonstrates in vivo (18)F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration. Acta Neuropathol 132:935-937|
Showing the most recent 10 out of 487 publications