AbstractsBiology & Animal Science

Alleviation of central accumulation of amyloid-beta and prevention of cognitive dysfunction following peripheral inflammation

by Marielle Kahn Weintraub

Institution: Texas Christian University
Year: 2014
Keywords: Alzheimer's disease Treatment.
Record ID: 2037890
Full text PDF: https://repository.tcu.edu/handle/116099117/4557


"Alzheimer's disease (AD) is characterized by neurodegeneration in regions of the adult brain, due to formation of amyloid-beta plaques and neurofibrillary tangles. Inflammation has been implicated in the onset and progression of these pathologies. Our previous studies resulted in an animal model of peripheral inflammation-induced AD-like pathology using the bacterial endotoxin lipopolysaccharide (LPS). Following 7 consecutive once-daily injections of LPS, C57BL/6J mice displayed significantly higher levels of amyloid-beta as well as cognitive deficits in hippocampus-dependent tasks. Here we explored multiple ways to alleviate the inflammation-induced central accumulation of amyloid-beta. Numerous studies have focused on reducing central amyloid-beta with pharmaceuticals designed to interfere with the mechanisms that lead to production of amyloid-beta, or by interfering with inflammation using non-steroidal anti-inflammatory drugs.^Non-pharmaceutical interventions, such as exercise, have also been studied and were found to be beneficial. The experiments described in this dissertation focused on three treatments that previously demonstrated possible therapeutic value for reducing central amyloid-beta accumulation. Treatment with Imatinib, an FDA approved drug for chronic myelogenous leukemia, resulted in decreased amyloid-beta accumulation and rescued cognitive deficits when the animals were first pre-treated for a week prior to LPS administration. In addition, our data suggests that the amyloid-beta production occurs in the periphery. Next, animals treated with Ibuprofen, a popular NSAID, did not appear to have altered amyloid-beta or reduced cognitive deficits. However, further testing is needed, as Ibuprofen has proven more effective when given for extended periods of time.^Finally, and most interestingly, two weeks of voluntary wheel running resulted in almost a complete elimination of central amyloid-beta, following LPS administration, while sedentary animals still showed significant elevation of central amyloid-beta. It is reasonable to assume that if the production of amyloid-beta could be reduced or eliminated from the brain there may be a potential for less susceptibility to the onset and detrimental effects of AD. Two of the three studies described above showed potential to be effective at reducing AD pathology. However, further studies need to be conducted in order to further understand the mechanism behind amyloid-beta removal and reduction" – Abstract.