2023, 2024
Tau is an abundant protein in neurons, where it stabilizes structures called microtubules. Alzheimer’s disease (AD) and related dementias are associated with a pathological transformation of tau (p-tau), which leads to it falling off the microtubule and translocating to the synapse, the region responsible for neuron-to-neuron communication and production of the chemical nitric oxide (NO). In a mouse model of increased brain tau, we found that p-tau binds to a special part of the synapse, the postsynaptic density protein 95 (PSD95). This prevents its association with nNOS, the enzyme that produces NO. As a result, less NO is made, which is damaging because it restricts neuronal communication and brain blood supply. PSD95 association with its partner proteins is controlled by modification with the fatty acid palmitate. In patients with p-tau accumulation, including those with AD, there are increased levels of fatty acid synthase (FASN), the enzyme responsible for palmitate production, raising the possibility that p-tau might increase PSD95 palmitoylation. Therefore, this proposal will test whether synaptic p-tau promotes PSD95 palmitoylation, which increases its association with p-tau—leading to a vicious cycle that disrupts nNOS-PSD95 binding and NO production. An enzyme, termed tissue plasminogen activator (tPA), is necessary for nNOS-dependent NO production at the synapse, and our pilot data indicate that it prevents p-tau-PSD95 binding. Therefore, we also will investigate whether tPA restores PSD95-nNOS binding, NO production and brain blood supply in models of p-tau accumulation. The proposed studies will shine light on an unexplored role of p-tau in synaptic dysfunction, and may open new avenues for the treatment of AD and other tauopathies based on the rescue of synaptic function by tPA.