Tau aggregation and its interplay with amyloid-β

Abstract

Neurofibrillary tangles and amyloid plaques constitute the hallmark brain lesions of Alzheimer’s disease (AD) patients. Tangles are composed of fibrillar aggregates of the microtubule-associated protein tau, and plaques comprise fibrillar forms of a proteolytic cleavage product, amyloid-β (Aβ). Although plaques and tangles are the end-stage lesions in AD, small oligomers of Aβ and tau are now receiving increased attention as they are shown to correlate best with neurotoxicity. One key question of debate, however, is which of these pathologies appears first and hence is upstream in the pathocascade. Studies suggest that there is an intense crosstalk between the two molecules and, based on work in animal models, there is increasing evidence that Aβ, at least in part, exerts its toxicity via tau, with the Src kinase Fyn playing a crucial role in this process. In other experimental paradigms, Aβ and tau have been found to exert both separate and synergistic modes of toxicity. The challenge, however, is to integrate these different scenarios into a coherent picture. Furthermore, the ability of therapeutic interventions targeting just one of these molecules, to successfully neutralize the toxicity of the other, needs to be ascertained to improve current therapeutic strategies, such as immunotherapy, for the treatment of AD. Although this article is not intended to provide a comprehensive review of the currently pursued therapeutic strategies, we will discuss what has been achieved by immunotherapy and, in particular, how the inherent limitations of this approach can possibly be overcome by novel strategies that involve single-chain antibodies.

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

“…We used a mouse model that expresses wild‐type human Tau and does not spontaneously produce Tau aggregates. In previous reports, the capability of Aβ1‐42 to induce Tau aggregation was studied in mice expressing mutant human Tau, models of tauopathies (Lewis et al ., 2001; Oddo et al ., 2006; Rhein et al ., 2009; Nisbet et al ., 2015). …”

“…6C. It is known that Aβ monomers, oligomers, and fibrils are in dynamic balance in AD brains (Nisbet et al ., 2015). …”

Does the difference between PART and Alzheimer’s disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?

“…Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau spread in an age-related manner from brainstem to cerebral cortical areas [3] and the presence of Aβ plaques is associated with acceleration in the propagation of NFTs in the pathogenesis of AD [11,18]. The amyloid cascade [8] appears to drive the hyperphosphorylation and propagation of tau [6,16] and Aβ oligomers have a toxic effect upon synapses [16].…”

Bidirectional Regulation of A beta Aggregates: Focus on Therapeutic Targets for Alzheimer's Disease

“…In the past decade, scFv-based immunotherapies have been reported to target various forms of protein aggregates including Aβ, SNCA, Htt, and PrP proteins [4]. A novel 2N tau isoform-specific scFv have been identified for experiment in a tau transgenic mouse model [5,6].…”