Abstract
BackgroundFrontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease. It involves atrophy of the frontal and temporal regions of the brain affecting language, memory, and behavior. Transactive response DNA-binding protein 43 (TDP-43) pathology is found in most FTD and ALS cases. It plays a role in transcription, translation and serves as a shuttle between the nucleus and cytoplasm. Prior to its aggregation, TDP-43 exists as polyubiquitinated, hyperphosphorylated C-terminal fragments that correlate well with FTD disease progression. Because of the importance of TDP-43 in these diseases, reagents that can selectively recognize specific toxic TDP variants associated with onset and progression of FTD can be effective diagnostic and therapeutic tools.ResultsWe utilized a novel atomic force microscopy (AFM) based biopanning protocol to isolate single chain variable fragments (scFvs) from a phage display library that selectively bind TDP variants present in human FTD but not cognitively normal age matched brain tissue. We then used the scFvs (FTD-TDP1 through 5) to probe post-mortem brain tissue and sera samples for the presence of FTD related TDP variants. The scFvs readily selected the FTD tissue and sera samples over age matched controls. The scFvs were used in immunohistochemical analysis of FTD and control brain slices where the reagents showed strong staining with TDP in FTD brain tissue slice. FTD-TDP1, FTD-TDP2, FTD-TDP4 and FTD-TDP5 all protected neuronal cells against FTD TDP induced toxicity suggesting potential therapeutic value.ConclusionsThese results show existence of different disease specific TDP variants in FTD individuals. We have identified a panel of scFvs capable of recognizing these disease specific TDP variants in postmortem FTD tissue and sera samples over age matched controls and can thus serve as a biomarker tool.
Highlights
Frontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease
We have identified a unique panel of Single chain variable fragment (scFv) capable of recognizing TDP variants that are present in human FTD patients but not in age-matched cognitively normal controls
Phage and scFv purification After serial rounds of subtractive panning were performed to remove phage that bound off target antigens including Bovine serum album (BSA), homogenate from healthy human brain tissue and Transactive response DNA-binding protein 43 (TDP-43) immunoprecipitated from pooled Amyotropic lateral sclerosis (ALS) brain tissue homogenates, a single round of positive selection was performed using immunoprecipitated TDP-43 from pooled FTD brain tissue (Fig. 1)
Summary
Frontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease It involves atrophy of the frontal and temporal regions of the brain affecting language, memory, and behavior. Transactive response DNA-binding protein 43 (TDP-43) pathology is found in most FTD and ALS cases. Frontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease [1]. PET scan that have shown promise in FTD diagnosis [7,8,9] These techniques have been demonstrated on a small scale and are focused on measuring anatomical similarities within FTD and assessing differences between FTD and other dementias. There is a need for biomarkers that can differentiate FTD from other diseases
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