The coming of age of selective types of autophagy for the treatment of Alzheimer´s disease and related tauopathies

Resum

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies, that include Alzheimer´s Disease (AD) and related forms of dementia, and affect around 44 million people worldwide. Autophagy dysfunction, one of the main intracellular pathways involved in tau degradation, together with oxidative stress and neuroinflammation are common features of these pathologies. However, the molecular mechanisms linking these processes and governing autophagy inhibition remain unclear. In this doctoral thesis, we have found that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA), a selective type of autophagy, whereas, upon acetylation, an early pathological event in neurodegeneration, tau is preferentially degraded by macroautophagy and endosomal microautophagy (e-MI). Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release and cell-to-cell spreading. Analysis of patients´ brains with tauopathies demonstrates similar molecular mechanism leading to CMA disfunction, and potentially contribute to disease progression. Furthermore, we also have found that hyperphosphorylation of tau, another pathogenic tau posttranslational modification, positively modifies macroautophagy at early-stages of tauopathy. However, at late-stages of the disease, macroautophagy eventually collapses prompting to neuronal toxicity and neurodegeneration in vivo. In this doctoral thesis, we also investigate unexplored therapeutic approximations to halt tau progression based on macroautophagy modulation. On one hand, NADPH oxidase 4 (NOX4), one of the main sources of reactive oxygen species (ROS) in the central nervous system (CNS), is upregulated in frontotemporal lobar degeneration (FTLD) and AD patients and in a humanized mouse model of tauopathy. In this context, both global knockout (KO) and neuronal knockdown (KD) of the Nox4 gene in mice reduce oligomeric tau accumulation by a mechanism that implicates modulation of macroautophagy flux and lysosomal activity, and reduction of oxidative stress and neuroinflammation. On the other hand, late treatment with supraphysiological doses of melatonin, positively modifies established tauopathy involving similar mechanisms. Overall, these results expand the knowledge about the interplay between pathogenic forms of tau and different autophagy pathways, provide novel molecular mechanisms underlaying autophagy disfunction and disease progression in tauopathy and highlight macroautophagy and lysosomal activity as key regulable mechanisms with disease-modifying effects for the treatment of AD and related tauopathies.