Anumala, Upendra Rao (2013)
Development of selective fluorescent imaging agents for neurofibrillary tangles in Alzheimer’s diagnosis.
Technische Universität Darmstadt
Dissertation, Erstveröffentlichung

Kurzbeschreibung (Abstract)

Alzheimer’s disease (AD) is a neurodegenerative disorder, a form of dementia that worsens over time. With the number of AD patients rising year by year, the total number of patients has already surpassed more than 25 million and this number will grow closer to 63 million by 2030. Symptoms of this disease include memory loss, challenges in problem solving, trouble in understanding visual images or spatial relationships and problems in speaking and writing. Current methods of detection rely on the minimal mental state examination. This is often inaccurate and cannot differentiate between AD and other forms of dementia. The two hallmarks that are responsible for AD are the formation of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. SPs are formed by the aggregation of insoluble amyloid beta protein and NFTs are formed by aggregation of hyperphosphorylated tau protein. In a healthy human brain, these two proteins are produced and broken down to small fragments and eliminated. In AD patients, SPs and NFTs are formed by aggregation of these two proteins. It is possible to image these SPs and NFTs by techniques such as positron emission tomography (PET) or fluorescence imaging which may enable early diagnosis of AD. Although, SP imaging is known, SP deposition does not correlate with the disease and is observed in healthy patients also, hence, a diagnosis of the disease based solely on SPs imaging is likely to be inaccurate. In addition to this, it is difficult to correlate the disease progression with senile plaque quantity in the brain. On the other hand, NFT formation known to correlate with the disease progression, and therefore, fluorescence imaging of such NFTs may reveal the disease progression. The present study describes a set of compounds able to visualize NFTs and SPs in a human AD brain obtained at autopsy. Several classes of compounds were synthesized and explored for their ability to stain NFTs, of these; rhodanine-3-acetic acids, 5H-imidazo [4,5-c] pyridine derivatives, bis(arylvinyl)pyrazine derivatives were identified as promising compounds for tau imaging. Our observations with these compounds showed us that thesecompounds bind to NFTs in an AD brain, which were clearly visualized by the fluorescence microscopy. In addition to this, selected compounds were tested for their cytotoxicity in hepatocellular carcinoma cell lines and zebrafish embryo development assay. These cytotoxicity studies indicated that these compounds display no or negligible cytotoxicity. Further, in vitro experiments of rhodanine-3-acetic acid derivatives in P30lS mice retina and in vitro experiments in human AD retina resulted in the absence of staining of retinal tissues. Remarkably, control tissues were stained with AT8 antibody. These results suggest that the tau aggregates in the retina of P301S mice are different from human tau deposits present in hyperphosphorylated NFTs. Further, in vitro experiments with 5H-imidazo [4,5-c] pyridine derivatives on olfactory epithelium tissues visualized tau deposits in olfactory epithelium tissues.

Frage zum Eintrag

Redaktionelle Details anzeigen