Axonal Spheroids and Conduction Defects in Alzheimer’s Disease: Mechanisms and Therapeutic Implications
Date of Award
Doctor of Philosophy (PhD)
Interdepartmental Neuroscience Program
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by widespread disruption in neural connectivity. One of the major pathological hallmarks of AD is the extracellular deposition of the β-amyloid (Aβ) peptide, which is thought to trigger a cascade of events, eventually leading to cognitive decline. However, the precise mechanisms linking Aβ deposition and neural network disruption are not well understood. Extensive previous work has focused on mechanisms such as cell death and synapse loss as potential substrates for neural dysfunction. However, a significant but understudied pathology in AD is the markedly enlarged neuronal processes found around Aβ deposits, here termed plaque-associated axonal spheroids (PAAS). Although various hypotheses regarding their development have been proposed through the years, these structures have not been a major focus of therapeutics and their pathophysiological significance remains uncertain.In this dissertation we undertook a multipronged approach to investigate PAAS, using high-resolution time-lapse intravital structural and calcium imaging, super-resolution expansion microscopy, single axon molecular manipulations and computational modeling. We found that axonal spheroids are prominent contributors to neural network dysfunction. PAAS leads to action potentials conduction blockades by acting as electric current sinks, leading to severe disruption in long-range axonal connectivity. The degree of disruption in axonal conduction was found to be determined by the size of individual spheroids. Mechanistically, we uncovered that the expansion of axonal spheroid was driven by an age-dependent accumulation of abnormally enlarged multivesicular bodies (MVBs). Furthermore, identification of the earlier mechanism of PAAS formation revealed that axonal spheroid forms through an aberrant sprouting and outgrowth process analogous to growth cones during neural development. Through adeno-associated virus (AAV)-mediated CRISPR/Cas9 deletion and overexpression strategies targeting individual axons, we demonstrated the possibility of preventing the initial formation and the subsequent expansion of PAAS. Importantly, this led to a marked improvement in interhemispheric axonal conduction properties, which is predicted to have a beneficial impact on neural network function and potentially on cognitive performance in Alzheimer’s disease.
Zhang, Mengyang, "Axonal Spheroids and Conduction Defects in Alzheimer’s Disease: Mechanisms and Therapeutic Implications" (2021). Yale Graduate School of Arts and Sciences Dissertations. 443.