Intersection of pathological tau and microglia at the synapse

Abstract

Tauopathies are a heterogenous class of diseases characterized by cellular accumulation of aggregated tau and include diseases such as Alzheimer's disease (AD), progressive supranuclear palsy and chronic traumatic encephalopathy. Tau pathology is strongly linked to neurodegeneration and clinical symptoms in tauopathy patients. Furthermore, synapse loss is an early pathological event in tauopathies and is the strongest correlate of cognitive decline. Tau pathology is additionally associated with chronic neuroinflammatory processes, such as reactive microglia, astrocytes, and increased levels of pro-inflammatory molecules (e.g. complement proteins, cytokines). Recent studies show that as the principal immune cells of the brain, microglia play a particularly important role in the initiation and progression of tau pathology and associated neurodegeneration. Furthermore, AD risk genes such as Triggering receptor expressed on myeloid cells 2 (TREM2) and Apolipoprotein E (APOE) are enriched in the innate immune system and modulate the neuroinflammatory response of microglia to tau pathology. Microglia can play an active role in synaptic dysfunction by abnormally phagocytosing synaptic compartments of neurons with tau pathology. Furthermore, microglia are involved in synaptic spreading of tau - a process which is thought to underlie the progressive nature of tau pathology propagation through the brain. Spreading of pathological tau is also the predominant target for tau-based immunotherapy. Active tau vaccines, therapeutic tau antibodies and other approaches targeting the immune system are actively explored as treatment options for AD and other tauopathies. This review describes the role of microglia in the pathobiology of tauopathies and the mechanism of action of potential therapeutics targeting the immune system in tauopathies.

Keywords: APOE4; Astrocytes; Complement; Microglia; Neurodegeneration; Neuroinflammation; Synaptic dysfunction; TREM2; Tau immunotherapy; Tau pathology.

Fig. 1

Major tau domains and phosphorylation sites. The amino acid sequence of the longest isoform of tau protein (2N4R, 1–441aa) in the central nervous system can be roughly divided into the projection domain on the N-terminal and the microtubule assembly domain on the C-terminal half of the protein. Tau can have up to two inserts in the N-terminal (here shown as N1, N2) and three or four repeats on the C-terminal (R1, R2, R3, R4). These combinations lead to a total of six different isoforms in the central nervous system. The VQIVYK sequence in R2 and VQIINK sequence in R3 are important for aggregation of tau. Several important phosphorylation sites that are associated with tau pathology are shown (p202/205, p212/214, p231, p396/404). These sites are targets for widely used antibodies such as AT8 or PHF1. Several C-terminal truncations have been identified that promote aggregation. Two wellcharacterized truncations are shown here (Δ391 and Δ421)

Fig. 2

a Several cell types are involved in tau-induced neuroinflammation. Neurons with tau pathology exposing phosphatidylserines can be live phagocytosed by microglia. Neuronal tau pathology also induces neuroinflammation by shedding myelin fragments, secreting stress factors, tau oligomers, or via other unknown pathways. In Alzheimer’s disease – the most common tauopathy – extracellular amyloid plaques also induce neuroinflammation. Tau oligomers can damage the vasculature directly, or indirectly via microglia-induced neuroinflammation or alterations of astrocytic functions at the vasculature. All these events can potentially lead to exacerbation of the neuroinflammatory state, which in turn can aggravate tau pathology via proinflammatory cytokines. Microglia can also induce a neurotoxic “A1” phenotype in astrocytes which directly leads to neurodegeneration. Astrocytes in primary tauopathies can also accumulate tau, which can lead to mild changes in the vasculature and possibly impact microglia and synaptic function. b Microglia and astrocytes play an important role in tau-induced synaptic dysfunction. Microglia can phagocytose synapses from neurons with tau pathology via the classical complement pathway. Microglia can also phagocytose secreted tau oligomers and spread them to healthy neuron in exosomes. Microglia in the healthy brain also play an important role in synapse homeostasis, for example via the secretion of cytokines or secretion of growth factors. Tau pathology could alter these homeostatic functions and lead to possible toxic gain-of-function. Astrocytes also play a critical role in synaptic function, for example by taking up extracellular glutamate, release of gliotransmitters that act on synaptic receptors, and secretion of factors that promote synapse assembly. Microglia in tauopathies can also alter the homeostatic functions of astrocytes, possibly leading to synaptic toxicity. Astrocytes with tau pathology can potentially also have deleterious effects on synaptic functions, but this is not yet studied and the role of microglia is therefore unclear