(This report is provided by Dr. Tu’s research team in the Department of Chemistry)
Of all patients with dementia across the globe, approximately 60-70% are confirmed cases of Alzheimer’s disease, the vast majority of which are seniors over the age of 65. New studies have suggested that around 30-57% of Alzheimer's patients were found to have abnormal levels of protein TDP-43 inclusions, which presents faster disease progression and greater brain atrophy. To this day, treatments for Alzheimer’s disease continue to be limited. Therefore, in order to develop better treatment strategies and gain a further understanding of the disease, the importance of TDP-43 must not be overlooked.
One of the distinctive characteristics found in the brains of patients diagnosed with Alzheimer's disease (AD) is the amyloid plaques composed of amyloid-β (Aβ) and Tau proteins. Many laboratories have further confirmed that the cluster of such proteins leads to damage to the nerve cells, which in turn causes brain atrophy and severe memory deficit. In recent years, however, new evidence has shown that aside from the aforementioned two types of proteins, TDP-43 has also been found to accumulate in the brains of AD patients in the form of insoluble plaques. Plaques of TDP-43 were first discovered in 2006 and began to draw attention after it was proven to be related to Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia. Amongst cases diagnosed with chronic traumatic encephalopathy, TDP-43 was found to have much higher protein expression than that of regular cases. Later, discoveries in AD began to draw high levels of attention to this topic. To further understand the disease's cause and its treatment possibilities,we began to study the relationship between TDP-43 and Aβ. (The project was first leaded by Dr. Ruby Chen at Genomics Research Center of the Academia Sinica)
Firstly, we have proven, through several biochemical and biophysical methods, that soluble TDP-43 is extremely prone to oligomerization, which heavily perturbs Aβ aggregation, delays fibrillization, and prolongs the lagtime of Aβ oligomers, which exacerbates its damage of nerve cells. We have also learned that the N-terminal domain (NTD) and residue 1–265 are the regions of TDP-43 that perturb Aβ the most, most likely because these two regions are capable of self-forming oligomers, which in turn affect Aβ. TDP-43_265 is likely present in the brains of AD patients, for past experiences have already proven that a calpain highly relevant to AD can be cleaved into full-length TDP-43 forms that contain 1-265 residues. Such observations are useful for us to understand how TDP-43 exacerbates AD pathology. Furthermore, experiments with mouse models have shown that mice injected with TDP-43 displayed lower levels of environmental and spacial orientation, and that TDP-43 and Aβ are indeed of an interactive relationship as they were found to clump together in the same plaques of the mice’s nerve cells, leading to severe inflammation of the mouse model’s brain. It would seem that the TDP-43 is in this regard playing the role of an accomplice, further complicating Alzheimer's disease .
The development of medicine and its treatment for human diseases has come a long way. However, without a proper understanding of its pathology or mechanism, a disease is as good as shrouded by an impenetrable veil where no medicine can take effect. AD is still a fog to researchers. Therefore, future studies will have to continue to investigate and scrutinize every possible lead until a breakthrough is discovered. Only then might we begin to get a chance to tackle neurodegenerative diseases.
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Reference: https://www.nature.com/articles/s41467-020-19786-7
