Resumen de Mecanismes moleculars implicats en la patologia de tau regulats per les presenilines en neurodegeneració
Alzheimer’s disease (AD), the most common cause of dementia worldwide, is characterized by gradual loss of cognition, especially memory, and behavioral and neuropsychiatric impairments. Neuropathological features of AD include amyloid-β (Aβ)-containing plaques, neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, neuronal loss, neuroinflammation and autophagic dysfunction, among others. In contrast to late-onset AD, most familial AD (FAD) cases are caused by dominantly inherited mutations in the Presenilin (PS/PSEN: PS1 and PS2) genes, the catalytic subunit of γ-secretase complex that is responsible for Aβ generation. Notably, mutations in PS1 are also linked to frontotemporal dementia (FTD) characterized by cerebral accumulation of aggregated phosphorylated tau but not amyloid plaques. Although the mechanisms by which PS mutations affect Aβ are well defined, the precise role of PS/γ-secretase on tau pathology independently of Aβ during neurodegeneration is largely unclear. The hypothesis of this doctoral thesis is that loss of PS function caused by dementia-linked mutations contributes to tau hyperphosphorylation, aggregation and/or spreading by affecting specific signaling and autophagy pathways. The objective of this study was to investigate the role of PS on tau pathology during synaptic dysfunction and neurodegeneration, and the mechanisms involved. To address this objective, I performed biochemical and structural protein analyses, including synchrotron infrared microspectroscopy, histological and behavioral approaches in novel neuronal-specific PS1 and double PS (PS1/PS2) conditional knockout (cKO) mice expressing either endogenous tau or overexpressing the FTD-linked (P301S) mutant human tau (Tau) gene. Our results show that loss of PS function results in age-dependent tau phosphorylation in the cortex and the hippocampus of PS cDKO mice associated with increased activation of p25/Cdk5, PKA/AMPK and Akt. As a result of neuronal PS inactivation, pathological phosphorylated tau accumulates in excitatory neurons, astrocytes, microglia, and oligodendrocytes. Interestingly, genetic inactivation of PS in human tau transgenic mice results in accelerated and enhanced tau phosphorylation and aggregation in memory and emotional neuronal circuits linked to AD pathology, including the entorhinal and restrosplenial cortices, hippocampus and amygdala, a phenotype associated to exacerbated memory and learning impairments. Biochemical analyses of purified synaptosomes from human AD and mouse transgenic brains also revealed abnormal synaptic accumulation of tau and decreased synaptic proteins and synaptonuclear factors (e.g., CRTC1) suggesting pre- and post-synaptic mechanisms impaired in brain of AD and AD mouse models. Remarkably, loss of PS function causes abnormally aggregated neurofilament protein together with increased aggregated and oligomeric β-sheet protein structures in PS1 cKO;Tau and PS cDKO;Tau mice. At the molecular level, I found that PS is required for correct mTOR activity and autophagic flux, maintaining autophagosome-lysosome fusion and tau degradation. Conversely, genetic inactivation of PS1 or both PS genes in human tau transgenic mice increases autophagic markers (LC3-II/I, p62…) and impairs and enhances phosphorylated and aggregated tau in autophagosomes. Taken together these results provide further evidence that partial loss of PS function leads to increased hyperphosphorylated and aggregated tau, inflammatory responses, and neurodegeneration, and that synapse dysfunction and memory deficits caused by PS inactivation suggest mediated by synaptic tau. Our findings could indicate that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PS mutations.
