P1‐005: SELECTIVELY ENHANCING PATHOLOGICAL FORMS OF TAU VIA THE AUTOPHAGY PATHWAY

Alzheimer's disease (AD) is the leading cause of neurodegeneration worldwide. Unfortunately, there are limited therapeutic options, due in part to an incomplete understanding of disease pathogenesis. One pathological hallmark of AD is the intracellular accumulation of hyperphosphorylated and truncated forms of the microtubule associated protein tau. These pathological forms of tau are unable to appropriately interact with microtubules, facilitatiing neuronal damage in AD. In addition, there are data to indicate that pathological tau, particularly in its oligomeric form, causes toxicity. Impairment of protein degradative systems is likely a contributing factor to the accumulation and aggregation of tau in AD. Therefore interventions that result in the selective upregulation of pathways that result in the clearance pathological tau without further diminishing the pool of available functional tau are of significant interest. Mouse cortical cells that inducibly express a single form of tau-unmodified, D421 truncation, phosphomimetic or phosphonull at T231 or S262-were established. Using these lines, degradation profiles for each form of tau were established both in the basal condition and in the presence of inhibitors or activators of the different protein degradation pathways. Primary neurons were used for complementary studies with phosphoepitope antibodies. Particular pathological forms of tau are preferentially cleared via the autophagy pathway. Additionally, activating the autophagy pathway leads to enhanced clearance of these potentially disease-mediating forms. Importantly, this process is specific. Treatment with trehalose, an activator of non mTor-dependent autophagy, is effective, while rapamycin is not. This may relate to the involvement of adaptor proteins that help chaperone pathological tau to autophagy. In particular, the adaptor protein NDP52 appears to be important. Expression of NDP52 is signaled by Nrf2, a transcription factor that can be activated by phytochemicals found in common foods. Treating primary neurons with a Nrf2 agonist enhances clearance of AD-specific phosphoforms of tau. The ability to specifically target pathological tau to degradation will facilitate removing toxic species from the cell while preserving the pool of normal tau that is critical for neuronal function. The use of Nrf2 agonists for this effect offers an exciting novel therapeutic target.