Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

Abstract

Neurofibrillary tangles, composed of insoluble aggregates of the microtubule-associated protein Tau, are a pathological hallmark of Alzheimer disease (AD) and other tauopathies. However, recent evidence indicates that neuronal dysfunction precedes the formation of these insoluble fibrillar deposits, suggesting that earlier prefibrillar Tau aggregates may be neurotoxic. To determine the composition of these aggregates, we have employed a photochemical cross-linking technique to examine intermolecular interactions of full-length Tau in vitro. Using this method, we demonstrate that dimerization is an early event in the Tau aggregation process and that these dimers selfassociate to form larger oligomeric aggregates. Moreover, using these stabilized Tau aggregates as immunogens, we generated a monoclonal antibody that selectively recognizes Tau dimers and higher order oligomeric aggregates but shows little reactivity to Tau filaments in vitro. Immunostaining indicates that these dimers/oligomers are markedly elevated in AD, appearing in early pathological inclusions such as neuropil threads and pretangle neurons as well as colocalizing with other early markers of Tau pathogenesis. Taken as a whole, the work presented herein demonstrates the existence of alternative Tau aggregates that precede formation of fibrillar Tau pathologies and raises the possibility that these hierarchical oligomeric forms of Tau may contribute to neurodegeneration.

Exosome-associated Tau Is Secreted in Tauopathy Models and Is Selectively Phosphorylated in Cerebrospinal Fluid in Early Alzheimer Disease

“…This difficulty, plus the lack of any secretion-associated motifs on tau, has fostered the assumption that tau secretion only occurs in association with nonphysiological tau overexpression and is thus irrelevant to tau pathobiology. However, recent demonstrations of high efficacy and specificity of tau secretion, toxicity, uptake, and interneuronal transfer in various tauopathy models (1)(2)(3)(4)(5)(6) and that these events and characteristics are modulated by disease-relevant tau alterations such as phosphorylation (3,(27)(28)(29)(30)(31), cleavage (34,38), and oligomerization (26,37,46,47) suggest that secretion may play a significant role in tau-associated neurodegeneration. The involvement of tau secretion in the genesis of increased CSF tau levels in the earliest stages of AD may therefore mark a significant change in our overall view of AD pathogenesis, both because of the new insights that it provides into disease-associated mechanisms of tau misprocessing and because of the potential clinical importance of tau secretion biomarkers for CSF-based AD diagnostics.…”

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…Indeed, we observed hTau‐A152T‐dependent neuronal loss in the hippocampus, consistent with findings obtained by Decker and colleagues 74. Mechanisms to explore in future studies include potential effects of the A152T substitution on (1) hTau/Fyn interactions 75, which could contribute to NMDA receptor‐mediated neurotoxicity 74, (2) network hyperexcitability 50, 76, and (3) tau's Gly 155 –Gln 244 region, which is exposed on the surface of tau oligomers 77 and might mediate interactions between these assemblies and cellular targets.…”

Alzheimer disease

“…72 Small oligomers, especially tau dimers, are intermediates in the filament assembly process. 44,73 Once filament polymerization has occurred, sonication can fracture the filaments into shorter, more numerous structures that can seed the assembly of additional tau monomers. 74 Tau filaments therefore have the ability to self-propagate.…”

“…Such oligomers have been detected immunologically in AD brain, most notably in neurons that had not yet accumulated NFTs. 73,77 Furthermore, intracerebral injection of tau oligomers, but neither monomeric nor fibrillar tau, has been shown to be neurotoxic, to cause synaptic and mitochondrial dysfunction, and to impair memory. 78…”