Tau immunotherapies for Alzheimer’s disease

Abstract

Introduction-Alzheimer's dementia (AD) is the most common form of dementia in the World. Pathologically, it is characterized by extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). The latter is composed of irregular, pathological forms of the tau protein. Currently, FDA-approved symptomatic treatments are limited to the targeting of cholinergic deficits and glutamatergic dysfunctions. However, as understanding of β-amyloid plaques and NFTs expands, these dysfunctional proteins represent potential therapeutic interventions. The present review article evaluates active and passive immunotherapies in clinical development for AD to date and their potential to significantly improve the treatment of AD going forward. Areas covered-All clinical trials that have targeted β-amyloid to date have produced somewhat disappointing results, leading to a shift in intervention focus to targeting tau protein. A key component in understanding the value of targeting tau in therapeutic paradigms has come from the conceptualization of prion-like pathological spread of tau isoforms from neuron to neuron, and referred to as 'tauons'. Immunotherapies currently under investigation include approaches aiming at preventing pathological tau aggregation, stabilizing microtubules, and blocking of tauons. Expert opinion-A multi-targeted approach that would use biologics targeting tau offers great promise to the development of effective AD therapeutic interventions.

Fate and propagation of endogenously formed Tau aggregates in neuronal cells

“…Nevertheless, we cannot exclude the fact that FLTau spreading via secretion modes could be more relevant in vivo when compared to our cell culture model. Previously described anti-Tau antibodies have been shown to impair uptake, seeding, or transfer (Funk et al, 2015;Nobuhara et al, 2017;Albert et al, 2019;Hoskin et al, 2019;Weisová et al, 2019;Roberts et al, 2020). However, it is worth noting that there is no direct evidence yet showing the presence of filamentous Tau in brain interstitial fluid of patients or in mouse models, although soluble Tau could be detected in that extracellular fluid (Clavaguera et al, 2009;Yamada et al, 2011;de Calignon et al, 2012;Plouffe et al, 2012;Dujardin et al, 2014;Goedert, 2015).…”

Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis

“…In addition, monoclonal antibody therapies that target Aβ have been met with difficulties in showing efficacy in human trials (van Dyck, 2018). Thus, the clinical failure of BACE inhibitors and Aβ antibodies in Alzheimer's disease over the last decade has led us to question the causal role of amyloidosis in disease pathology and cognitive decline, and may even have spurred a shift in therapeutic focus towards targeting tauopathies (or tauons) (Moussa-Pacha et al, 2019;Hoskin et al, 2019). Confusion as to the causes and treatment of Alzheimer's disease has been further exacerbated by the recent re-designation of ∼20% of older Alzheimer's disease patients as having a different type of dementia caused by TDP-43 proteinopathy, called limbic-predominant agerelated TDP-43 encephalopathy (LATE) (Nelson et al, 2019).…”

Dreaming of a New World Where Alzheimer’s Is a Treatable Disorder

“…Initially, anti-tau therapies were based mainly on inhibition of kinases or tau aggregation or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy (Congdon and Sigurdsson, 2018). Immunotherapy against tau is now under evaluation in clinical trials as an approach potentially able to interfere with more than one of the above-cited mechanistic events (Hoskin et al, 2019). However, current tau-based immunotherapy programs are raising additional questions concerning the choice of the most efficient epitopes, the induction of extracellular vs. intracellular clearance of tau protein, the strength of the affinity of mAbs for tau, which can deeply modify the efficacy and safety of tau-targeting strategy (Golde, 2014; Pedersen and Sigurdsson, 2015; Sigurdsson, 2016).…”