Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology.

Tau protein, a neuronal microtubule-associated protein, becomes hyperphosphorylated in several neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau is correlated to its redistribution from the axon to the somato-dendritic compartment at early stages of tauopathies. Interestingly, tau hyperphosphorylation begins in different regions of the brain in each tauopathy. In some regions, both neurons and glial cells develop tau hyperphosphorylation. Tau hyperphosphorylation is also observed in physiological conditions such as hibernation and brain development. In the first section of present article, we will review the spatiotemporal and cellular distribution of hyperphosphorylated tau in the most frequent tauopathies. In the second section, we will compare the pattern of tau hyperphosphorylation in physiological and pathological conditions and discuss the sites that could play a pivotal role in the conversion of non-toxic to toxic forms of hyperphosphorylated tau. Furthermore, we will discuss the role of hyperphosphorylated tau in physiological and pathological conditions and the fact that tau hyperphosphorylation is reversible in physiological conditions but not in a pathological ones. In the third section, we will speculate how the differences and similarities between hyperphosphorylated tau in physiological and pathological conditions could impact the elaboration of therapies to prevent tau pathology. In the fourth section, the different therapeutic approaches using tau as a direct or indirect therapeutic target will be presented.

Clearance of intracellular tau protein from neuronal cells via VAMP8-induced secretion.

In Alzheimer's disease (AD), tau, a microtubule-associated protein (MAP), becomes hyperphosphorylated, aggregates, and accumulates in the somato-dendritic compartment of neurons. In parallel to its intracellular accumulation in AD, tau is also released in the extracellular space, as revealed by its increased presence in cerebrospinal fluid (CSF). Consistent with this, recent studies, including ours, have reported that neurons secrete tau, and several therapeutic strategies aim to prevent the intracellular tau accumulation. Previously, we reported that late endosomes were implicated in tau secretion. Here, we explore the possibility of preventing intracellular tau accumulation by increasing tau secretion. Using neuronal models, we investigated whether overexpression of the vesicle-associated membrane protein 8 (VAMP8), an R-SNARE found on late endosomes, could increase tau secretion. The overexpression of VAMP8 significantly increased tau secretion, decreasing its intracellular levels in the neuroblastoma (N2a) cell line. Increased tau secretion by VAMP8 was also observed in murine hippocampal slices. The intracellular reduction of tau by VAMP8 overexpression correlated to a decrease of acetylated tubulin induced by tau overexpression in N2a cells. VAMP8 staining was preferentially found on late endosomes in N2a cells. Using total internal reflection fluorescence (TIRF) microscopy, the fusion of VAMP8-positive vesicles with the plasma membrane was correlated to the depletion of tau in the cytoplasm. Finally, overexpression of VAMP8 reduced the intracellular accumulation of tau mutants linked to frontotemporal dementia with parkinsonism and α-synuclein by increasing their secretion. Collectively, the present data indicate that VAMP8 could be used to increase tau and α-synuclein clearance to prevent their intracellular accumulation.

Tau Secretion: Good and Bad for Neurons.

In Alzheimer's disease (AD), neurofibrillary tangles (NFTs), lesions composed of hyperphosphorylated and aggregated tau, spread from the transentorhinal cortex to the hippocampal formation and neocortex. Growing evidence indicates that tau pathology propagates trans-synaptically, implying that pathological tau released by pre-synaptic neurons is taken up by post-synaptic neurons where it accumulates and aggregates. Observations such as the presence of tau in the cerebrospinal fluid (CSF) from control individuals and in the CSF of transgenic mice overexpressing human tau before the detection of neuronal death indicate that tau can be secreted by neurons. The increase of tau in the CSF in pathological conditions such as AD suggests that tau secretion is enhanced and/or other secretory pathways take place when neuronal function is compromised. In physiological conditions, extracellular tau could exert beneficial effects as observed for other cytosolic proteins also released in the extracellular space. In such a case, blocking tau secretion could have negative effects on neurons unless the mechanism of tau secretion are different in physiological and pathological conditions allowing the prevention of pathological tau secretion without affecting the secretion of physiological tau. Furthermore, distinct extracellular tau species could be secreted in physiological and pathological conditions, species having the capacity to induce tau pathology being only secreted in the latter condition. In the present review, we will focus on the mechanisms and function of tau secretion in both physiological and pathological conditions and how this information can help to elaborate an efficient therapeutic strategy to prevent tau pathology and its propagation.

Opposite control of frontocortical 2-arachidonoylglycerol turnover rate by cannabinoid type-1 receptors located on glutamatergic neurons and on astrocytes.

This study examined the respective influences of cannabinoid type-1 (CB1) receptors expressed either in forebrain GABAergic neurons, in cortical glutamatergic neurons, or in astrocytes on the turnover rates of the endocannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), and the non-cannabinoid N-acylethanolamides, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), in mouse forebrain regions. To this end, conditional mutant mice lacking CB1 receptors from either of these cell types were pre-treated systemically with JZL195, a dual inhibitor of fatty acid amide hydrolase, the enzyme degrading AEA, PEA, and OEA, and of monoacylglycerol lipase, the main 2-AG-degrading enzyme. The analyses of frontocortical, hippocampal, and striatal AEA, 2-AG, PEA, and OEA concentrations revealed that their respective baseline concentrations were not influenced by the mouse genotype. On the other hand, the accumulation of frontocortical and/or hippocampal 2-AG levels in JZL195-pre-treated mice was dependent on the mouse genotype. Thus, JZL195-induced 2-AG accumulation rates were diminished in the frontal cortex of mice lacking CB1 receptors in glutamatergic neurons while their respective values were increased in the frontal cortex and hippocampus of mice lacking these receptors in astrocytes. These genotypic differences occurred with parallel and proportionate changes in the fractional rate constants for degradation of 2-AG, thus providing a mechanism whereby the baseline levels of 2-AG remained constant between genotypes. Besides suggesting a cell-type-specific control of frontocortical and/or hippocampal 2-AG synthesis and degradation rates by CB1 receptors, this study highlights the interest of assessing endocannabinoid turnover rates when questioning the status of the endocannabinoid system.