Microtubule Dynamics in Tau-dependent Amyloid Beta Synaptotoxicity

Alzheimer’s disease is the most common form of dementia among older adults, and directly contributes to the third leading cause of death in the United States. Although amyloid plaques and tau-loaded neurofibrillary tangles have been identified as the main pathological features of Alzheimer’s disease for more than one hundred years, the molecular mechanism is still poorly understood and treatments are limited to palliative care. Oligomeric Amyloid beta plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Amyloid beta toxicity, but the link between the two remains controversial. Since tau is a microtubule associated protein and microtubules are critical for neuronal functions, regulation of dynamic microtubules may serve as the link between Amyloid beta and tau. Here I propose a model in which Amyloid beta can induce changes in MT dynamics in dendrites and axons that are primary to tau hyperphosphorylation, while these MT changes are sufficient to cause tau hyperphosphorylation and necessary for Amyloid beta synaptotoxicity through tau. My thesis work further characterizes mammalian excitatory presynaptic boutons as hotspots for activity-dependent dynamic microtubule nucleation that is required for synaptic transmission during neuronal activation or Amyloid beta-induced neuronal injury through tau.