Amyloid-β (Aβ) accumulation is one of the major pathological hallmarks of Alzheimer’s disease (AD). It is known that, in adult healthy brain, resident macrophages of the central nervous system called microglia are essential for clearing misfolded proteins like Aβ by engulfing the prey particles during phagocytosis by forming extended cellular processes. Microglial phagocytosis is essential to regulate brain function during health and disease. Impaired phagocytic function is related to the onset of AD and likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain poorly understood due to the lack of available tools. We have developed a well-characterized, human Aβ1–42 analogue (AβpH) that exhibits green fluorescence upon internalization into the acidic organelles of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of Aβ pH in real-time in live animals. We find that microglia phagocytose more Aβ pH than astrocytes in culture, in brain slices, and in vivo. Aβ pH can be used to investigate the phagocytic mechanisms responsible for removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of AD. In a similar manner, the development of pH-activable cell organelle targeting fluorescent probes will help control specific biochemical processes in live cells. To this end, we have developed a modular one-step synthetic strategy using a common reaction intermediate to obtain new lysosomal, mitochondrial and nucleus targeting pH-activable fluorescent probes based on a single boron dipyrromethane analogs. The divergent cell organelle targeting was achieved by synthesizing pH-activable fluorescent probes with specific functional group changes to the main scaffold resulting in differential fluorescence and pKa and show how functional transformation affects the cellular localization. We introduce a structure-organelle-relationship (SOR) framework targeting the nucleus, lysosomes, and mitochondria in primary mouse microglial cells. This work will result in future applications of SOR beyond imaging to target and control organelle-specific biochemical processes in disease-specific models.

pH-Responsive chemical tools for glial cells

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.