Juan Ramón Perea

Alzheimer’s disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies. We previously demonstrated that extracellular soluble tau triggers p38 MAPK activation in microglia. Given the activation of this signaling pathway in AD and its involvement in neuroinflammation processes, here we evaluated the effect of p38 inhibition on primary microglia cultures subjected to tau treatment. Our data showed that the toxic effect driven by tau in microglia was diminished through p38 inhibition. Furthermore, p38 blockade enhanced microglia-mediated tau phagocytosis, as reflected by an increase in the number of lysosomes. In conclusion, these results contribute to our understanding of the functions of p38 in the central nervous system (CNS) beyond tau phosphorylation in neurons and provide further insights into the potential of p38 inhibition as a therapeutic strategy to halt neuroinflammation in tauopathies.

Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

Tau is a microtubule-associated protein that is expressed in neurons. However, in a group of neurodegenerative diseases named tauopathies – characterized by an increase in aggregated and/or hyperphosphorylated Tau – the protein accumulates inside other cells, such as astrocytes and microglia. Given that these glial cells do not produce Tau, its presence can be explained by internalization from the extracellular medium and consequent formation of Tau aggregates. Among internalization mechanisms, heparan sulfate proteoglycans (HSPGs) have been proposed to be responsible for fibrillary Tau uptake in various cell types. Here we studied whether monomeric Tau, which has been observed to be internalized by glial cells such as microglia, was also taken up by astrocytes. Although this Tau form was internalized from the extracellular medium by these cells, the mechanism of uptake was found to be independent of HSPGs.

Newborn dentate granule cells (DGCs) are generated in the hippocampal dentate gyrus (DG) of rodents through a process called adult hippocampal neurogenesis (AHN), which is subjected to tight intrinsic and extrinsic regulation. The use of retroviruses encoding fluorescent proteins has allowed the characterization of the maturation dynamics of newborn DGCs, including their morphological development and the establishment and maturation of their afferent and efferent synaptic connections. However, the study of a crucial cellular compartment of these cells, namely the axon initial segment (AIS), has remained unexplored to date. The AIS is not only the site of action potential initiation, but it also has a unique molecular identity that makes it one of the master regulators of neural plasticity and excitability. Here we examined the dynamics of AIS formation in newborn DGCs of young female adult C57BL/6J mice in vivo. Our data reveal notable changes in AIS length and thickness throughout cell maturation under physiological conditions and show that the most remarkable structural changes coincide with periods of intense morphological and functional remodeling. Moreover, we demonstrate that AIS development can be modulated extrinsically by both neuroprotective (environmental enrichment) and detrimental (lipopolysaccharide from E. coli) stimuli. SIGNIFICANCE STATEMENT The hippocampal dentate gyrus (DG) of rodents generates newborn dentate granule cells (DGCs) throughout life. This process, named adult hippocampal neurogenesis (AHN), confers a unique degree of plasticity to the hippocampal circuit and it is crucial for learning and memory. Here we studied, for the first time, the formation of a key cellular compartment of newborn DGCs, namely the axon initial segment (AIS) in vivo. Our data reveal remarkable AIS structural remodeling throughout the maturation of these cells under physiological conditions. Moreover, AIS development can be modulated extrinsically by both neuroprotective (environmental enrichment) and detrimental (lipopolysaccharide from E. coli) stimuli.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the presence of neurofibrillary tangles, constituted by tau protein, and plaques formed by amyloid-beta protein. The disease courses with high neural damage, which leads to memory loss and death. Here we analyzed the presence of CX3CL1, a chemokine expressed by neurons, in cerebrospinal fluid (CSF) samples from control subjects and patients with mild cognitive impairment and AD dementia. CX3CL1 was decreased in the CSF of AD dementia patients compared to control subjects. However, there was not difference in plasma samples from the same subjects.

Tauopathies are neurodegenerative diseases which course with the accumulation of Tau, mainly in neurons. In addition, Tau accumulates in a hyperphosphorylated and aggregated form. This protein is released into the extracellular space and spreads following a stereotypical pattern, inducing the development of the disease through connected regions of the brain. Microglia—the macrophages of the brain—are involved in maintaining brain homeostasis. They perform a variety of functions related to the surveillance and clearance of pathological proteins, among other dead cells and debris, from the extracellular space that could compromise brain equilibrium. This review focuses on the role played by microglia in tauopathies, specifically in Alzheimer’s disease (AD), and how the uncoupling of activation/phagocytosis functions can have fatal consequences leading to the development of the pathology.

Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses. Furthermore, the use of an RFP-expressing retrovirus revealed that soluble Tau altered the morphology of newborn granule neurons and reduced their afferent (dendritic spines) and efferent (mossy fiber terminals) connectivity. Finally, soluble Tau caused specific impairment of behavioral pattern separation capacity. Our results thus demonstrate for the first time that soluble Tau causes long-term detrimental effects on the morphology and connectivity of newborn granule neurons and that these effects correlate with impaired behavioral pattern separation skills. These data might be relevant for the field of neurodegenerative disorders, since they contribute to reinforcing the pathological roles played by distinct Tau species in vivo.

Molecular changes associated with neuronal aging lead to a decrease in cognitive capacity. Here we discuss these alterations at the level of brain regions, brain cells, and brain membrane and cytoskeletal proteins with an special focus in NMDA molecular changes through aging and its effect in cognitive decline and Alzheimer disease. Here, we propose that some neurodegenerative disorders, like Alzheimer’s disease, are characterized by an increase and acceleration of some of these changes.