Frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD) is a group of heterogeneous sporadic and familial neurodegenerative disorders. They are the second most common cause of dementia after Alzheimer's disease (AD) in patients <65 and ~50% of FTLD patients develop abundant tau pathologies in neurons and glia (FTLD-Tau). Exciting new data from Project 2 and provocative recent reports provide models to test novel hypothesis concerning mechanisms of tauopathies. The first hypothesis we test is based on our recent observations that introduction of small amounts of exogenous tau fibril "seeds" into tau overexpressing cells recruits endogenous tau to fibrillize into abundant tau filamentous structures seeded by the exogenously introduced tau fibrils. These results suggest a "seeding" mechanism of tau tangle pathogenesis whereby fibrillar tau "seeds" serve as a "nidus" for recruiting soluble tau into fibrillar aggregates that enlarge as a result. The second hypothesis we test is based on recent data that tau fibrils spread from cell-to-cell in vitro and in tau transgenic (Tg) mouse models consistent with the notion of a prion-like mechanism for the propagation and spreading of tau pathology and disease progression. Successful completion of the studies to test these hypotheses here will address fundamental disease mechanisms of FTLD-Tau, which, in conjunction with research advances from other projects in this PPG will accelerate efforts to find better therapeutic interventions for patients with diverse FTLDs.
Project 2 will provide in depth understanding on the fundamental disease mechanisms for tauopathies in general and FTLD-Tau in particular. This knowledge, together with the model systems developed in Project 2 will accelerate efforts to develop more effective therapies for the treatment of patients with FTLD-Tau and other tauopathies such as AD.
|Russ, Jenny; Liu, Elaine Y; Wu, Kathryn et al. (2015) Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129:39-52|
|Massimo, Lauren; Evans, Lois K (2014) Differentiating subtypes of apathy to improve person-centered care in frontotemporal degeneration. J Gerontol Nurs 40:58-65|
|Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A et al. (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol 13:686-99|
|Olm, Christopher A; McMillan, Corey T; Spotorno, Nicola et al. (2014) The relative contributions of frontal and parietal cortex for generalized quantifier comprehension. Front Hum Neurosci 8:610|
|Serrano, Geidy E; Sabbagh, Marwan N; Sue, Lucia I et al. (2014) Positive florbetapir PET amyloid imaging in a subject with frequent cortical neuritic plaques and frontotemporal lobar degeneration with TDP43-positive inclusions. J Alzheimers Dis 42:813-21|
|Irwin, David J; McMillan, Corey T; Suh, EunRan et al. (2014) Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia. Neurology 83:502-9|
|Alfieri, Julio A; Pino, Natalia S; Igaz, Lionel M (2014) Reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies. J Neurosci 34:15244-59|
|Walker, Adam K; Daniels, Christine M LaPash; Goldman, James E et al. (2014) Astrocytic TDP-43 pathology in Alexander disease. J Neurosci 34:6448-58|
|McCluskey, Leo F; Geser, Felix; Elman, Lauren B et al. (2014) Atypical Alzheimer's disease in an elderly United States resident with amyotrophic lateral sclerosis and pathological tau in spinal motor neurons. Amyotroph Lateral Scler Frontotemporal Degener 15:466-72|
|Bit-Ivan, Esther N; Suh, Eunran; Shim, Hyung-Sub et al. (2014) A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases. J Neuropathol Exp Neurol 73:467-73|
Showing the most recent 10 out of 333 publications