Abstract
Tauopathies are a group of neurodegenerative diseases characterized by the alteration/aggregation of TAU protein, for which there is still no effective treatment. Therefore, new pharmacological targets are being sought, such as elements of the endocannabinoid system (ECS). We analysed the occurrence of changes in the ECS in tauopathies and their implication in the pathogenesis. By integrating gene expression analysis, immunofluorescence, genetic and adeno-associated virus expressing TAU mouse models, we found a TAU-dependent increase in CB2 receptor expression in hippocampal neurons, that occurs as an early event in the pathology and was maintained until late stages. These changes were accompanied by alterations in the endocannabinoid metabolism. Remarkably, CB2 ablation in mice protects from neurodegeneration induced by hTAUP301L overexpression, corroborated at the level of cognitive behaviour, synaptic plasticity, and aggregates of insoluble TAU. At the level of neuroinflammation, the absence of CB2 did not produce significant changes in concordance with a possible neuronal location rather than its classic glial expression in these models. These findings were corroborated in post-mortem samples of patients with Alzheimer’s disease, the most common tauopathy. Our results show that neurons with accumulated TAU induce the expression of the CB2 receptor, which enhances neurodegeneration. These results are important for our understanding of disease mechanisms, providing a novel therapeutic strategy to be investigated in tauopathies.
Highlights
TAU protein is the major component of the intracellular filamentous deposits that characterize several neurodegenerative diseases termed tauopathies, which include Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD-TAU), progressive supranuclear palsy, corticobasal degeneration, among others [42]
Our results indicated that hTAUP 301S overexpression induced significantly Cnr2 mRNA expression in late stages of the pathology (9.44 ± 1.54) (Fig. 1a) and this change appears to be dependent on the presence of this mutant TAU form and its potential to aggregate
Previous evidence from our laboratory indicated that overexpression of hTAUP301L induced a neuroinflammatory process [17, 21, 39], which is a key hallmark in the neuronal degeneration in tauopathies [41]
Summary
TAU protein is the major component of the intracellular filamentous deposits that characterize several neurodegenerative diseases termed tauopathies, which include Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD-TAU), progressive supranuclear palsy, corticobasal degeneration, among others [42]. MAPT gene underlying familial frontotemporal dementia (FTD), such as TAUP 301L or TAUP 301S, have supported the generation of multiple mouse models that recapitulate pathological and/or behavioural aspects of this disease. These TAU mutations reduce the ability of the protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. There are other tauopathies where the dysregulation of TAU protein derives from different posttranslational changes, e.g. hyperphosphorylation, inducing the formation of neurofibrillary tangles, harmful to the neuron, as in the case of AD. The failure of different clinical trials with drugs targeting
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