Search

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.

Microtubules play fundamental roles in the maintenance of neuronal processes and in synaptic function and plasticity. While dynamic microtubules are mainly composed of tyrosinated tubulin, long-lived microtubules contain detyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination cycle is a key player in the maintenance of microtubule dynamics and neuronal homeostasis, conditions that go awry in neurodegenerative diseases. In the tyrosination/detyrosination cycle, the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidases and re-added by tubulin tyrosine ligase (TTL). Here we show that TTL heterozygous mice exhibit decreased tyrosinated microtubules, reduced dendritic spine density and both synaptic plasticity and memory deficits. We further report decreased TTL expression in sporadic and familial Alzheimer’s disease, and reduced microtubule dynamics in human neurons harbouring the familial APP-V717I mutation. Finally, we show that synapses visited by dynamic microtubules are more resistant to oligomeric amyloid-β peptide toxicity and that expression of TTL, by restoring microtubule entry into spines, suppresses the loss of synapses induced by amyloid-β peptide. Together, our results demonstrate that a balanced tyrosination/detyrosination tubulin cycle is necessary for the maintenance of synaptic plasticity, is protective against amyloid-β peptide-induced synaptic damage and that this balance is lost in Alzheimer’s disease, providing evidence that defective tubulin retyrosination may contribute to circuit dysfunction during neurodegeneration in Alzheimer’s disease.