Browsing by Author "Gwei, Schuyler"

Alzheimer’s Disease (AD) is a neurodegenerative disease affecting tens of millions of lives worldwide, and is characterized by protein aggregations called amyloid-β (Aβ) plaques and neuroimmune dysregulation. Recent research has found that 40 Hz gamma entrainment reduces Aβ load in mice, and other work has proposed that IFN-γ, an important cytokine involved in neuroimmune signalling, could increase the breakdown of Aβ plaques. Previous work out of Dr. Felipe Schiffino’s lab has corroborated and connected these findings by revealing that optogenetically induced 40 Hz gamma entrainment increases both Aβ uptake and IFN-γ levels in an AD mouse model—however, the pathway through which these increases are generated is still unclear. ICAM is a protein found in the blood-brain-barrier (BBB) responsible for mediating immune cell infiltration, and has previously been shown to be dysfunctional during AD progression. ICAM regulation is potentially implicated in our optogenetic model through neurovascular coupling, making its expression an important site for beginning to elucidate how gamma entrainment might upregulate microglial Aβ uptake and IFN-γ signalling. This research aims to consider the BBB and neuroimmune response as potential sites of repair or modulation during 40 Hz gamma optogenetic treatment of an AD mouse model. Using immunohistochemistry (IHC) for qualitative (visual inspection) and quantitative analysis, factors involved in immune cell transmigration across the BBB during AD pathogenesis were considered, including Aβ plaques, vasculature, ICAM, and immune cells. The results revealed that the optogenetic treatment did not significantly alter expression of any of these factors of interest, aligning most closely with the proposed peripheral hypothesis, which posits that increased microglial Aβ uptake is driven by IFN-γ released into the brain parenchyma from T cells in the periphery, thus not involving increased ICAM expression or immune infiltration. However, large data spread throughout the experiments reduces the reliability of these findings and constrains our interpretations of some of the trends in the data (none of which were statistically significant). Future work must utilize larger comparison groups to obtain sufficient statistical power so as to achieve a greater understanding of how this optogenetic treatment model might impact the BBB and neuroimmune axis.