Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD) and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease.Keywords: Alzheimer's disease, Tauopathies, Neurofibrillary degeneration, Neuroinflammation, Microglia Neurodegenerative niche in the ocean of the brain inflammationAlzheimer's disease (AD), the major cause of dementia, is characterized by the aberrant folding of the protein tau, leading to its intracellular and extracellular accumulation and to β-amyloidosis seen as extracellular deposits of β-amyloid (Aβ) in the brain parenchyma and around cerebral blood vessels [1][2][3][4][5][6][7][8]. Although it is well-documented that Aβ deposition is considered to be an important inducer of the chronic inflammatory response driven by activated microglia and astrocytes [9][10][11][12], little is known about the role of misfolded tau in the neuroinflammatory cascade. In AD, the pathological lesions of misfolded tau are present as intracellular and extracellular neurofibrillary tangles, neuropil threads and neuritic plaques [6,7]. Interestingly, several independent studies have revealed that the regional distribution and load of neurofibrillary lesions parallel the distribution of reactive microglia in AD [13,14]. In an extensive histopathological study published by Irina Alafuzoff's group, it was shown that ApoE genotype significantly influenced the linkage between neurofibrillary tangles (NFTs) and activated microglia. Furthermore, the authors clearly demonstrated that microglial upregulation of major histocompatibility complex class II antigen (HLA-DR) increased the duration of AD and correlated with NFT counts in sporadic cases, but not in familial o...

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BackgroundAbnormal misfolded tau protein is a driving force of neurofibrillary degeneration in Alzheimer’s disease. It has been shown that tau oligomers play a crucial role in the formation of intracellular neurofibrillary tangles. They are intermediates between soluble tau monomers and insoluble tau filaments and are suspected contributors to disease pathogenesis. Oligomeric tau can be released into the extracellular space and spread throughout the brain. This finding opens the question of whether brain macrophages or blood monocytes have the potential to phagocytose extracellular oligomeric tau.MethodsWe have used stable rat primary microglial cells, rat peripheral monocytes-derived macrophages, BV2 microglial and TIB67 macrophage immortalized cell lines that were challenged by tau oligomers prepared by an in vitro aggregation reaction. The efficiency of cells to phagocytose oligomeric protein was evaluated with confocal microscopy. The ability to degrade tau protein was analyzed by immunoblotting.ResultsConfocal microscopy analyses showed that macrophages were significantly more efficient in phagocytosing oligomerized tau proteins than microglial cells. In contrast to macrophages, microglia are able to degrade the internalized oligomeric tau only after stimulation with lipopolysaccharide (LPS).ConclusionsOur data suggests that microglia may not be the principal phagocytic cells able to target extracellular oligomeric tau. We found that peripheral macrophages display a high potency for elimination of oligomeric tau and therefore could play an important role in the modulation of neurofibrillary pathology in Alzheimer’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0161-z) contains supplementary material, which is available to authorized users.

Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer’s disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.