Potential mechanisms and implications for the formation of tau oligomeric strains

Abstract

The culmination of many years of increasing research into the toxicity of tau aggregation in neurodegenerative disease has led to the consensus that soluble, oligomeric forms of tau are likely the most toxic entities in disease. While tauopathies overlap in the presence of tau pathology, each disease has a unique combination of symptoms and pathological features, however, most study into tau has grouped tau oligomers and studied them as a homogenous population. Established evidence from the prion field combined with the most recent tau and amyloidogenic protein research suggests that tau is a prion-like protein, capable of seeding the spread of pathology throughout the brain. Thus, it is likely that tau may also form prion-like strains or diverse conformational structures that may differ by disease and underlie some of the differences in symptoms and pathology in neurodegenerative tauopathies. The development of techniques and new technology for the detection of tau oligomeric strains may therefore lead to more efficacious diagnostic and treatment strategies for neurodegenerative disease.

A novel small molecule screening platform for disrupting toxic tau oligomers in cells

“…Indeed, it is unlikely that a single, unique toxic conformation exists. It is far more likely that an ensemble of toxic oligomers (differing in size, conformation and even molecular constituency) populates the amylogenic cascade [29][30][31][32][33][34][35] . This heterogeneity in potential tau oligomer targets highlights the need for an ultrasensitive screening platform capable of monitoring structural changes within the ensemble of tau assemblies.…”

“…However, these studies were done in vitro with purified proteins, and the compounds were protective only in the low micromolar range [22][23][24][25][26][27][28] . Tau oligomers exist as an ensemble of distinct assemblies which include both toxic and non-toxic, onand off-pathway species along the fibrillogenesis cascade [29][30][31][32][33][34][35] . The formation of these toxic tau oligomers has been associated with mutations and overexpression of numerous chaperone proteins [36][37] , highlighting the importance of other components of the tau-protein interactome in the pathogenesis of tauopathies.…”

“…The formation of these toxic tau oligomers has been associated with mutations and overexpression of numerous chaperone proteins [36][37] , highlighting the importance of other components of the tau-protein interactome in the pathogenesis of tauopathies. Capturing this complexity in an in vitro setting is extremely difficult, if even possible, and established protocols for aggregating purified tau protein into oligomers, PHFs, and NFTs have, not surprisingly, been shown to produce different tau assemblies depending on aggregation conditions 17,31,34,[38][39][40][41] . Critically, no specific toxic tau species has been isolated or identified to date 21,[42][43] .…”

Ovarian hormones, genes, and the brain: the case of estradiol and the brain-derived neurotrophic factor (BDNF) gene

“…The BDNF gene is of particular interest for investigating gene-hormone interaction because estradiol induces BDNF expression that mediates hippocampal function [1]. Likely as a consequence, in female BDNF Met knock-in mice, the estrus cycle critically interacts with the Val 66 Met variant to modulate anxiety-related behaviors [2] as well as hippocampally dependent function and behavior [3].…”

“…For example, depressive episodes seem to predominate bipolar illness episodes in women, whereas in men, mania is more frequent [1]. There are also sex differences in management of medication side effects and comorbidities [2], and women with bipolar disorder report poorer sleep quality, which predicts more intense mood symptoms [3]. An oft-cited but poorly understood phenomenon in bipolar disorder is antidepressant-induced mania (AIM) or antidepressant emergent manic symptoms (AEMS).…”