Tau immunization: a cautionary tale?

Mably, Alexandra J.; Kanmert, Daniel; Donald, Jessica M. Mc; Li, Wen; Caldarone, Barbara J.; Lemere, Cynthia A.; O’Nuallain, Brian; Kosik, Kenneth S.; Walsh, Dominic M.

doi:10.1016/j.neurobiolaging.2014.11.022

Cited by 28 publications

(35 citation statements)

References 104 publications

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“…A separate aliquot of ADDLs (50 l) was thawed and loaded on to a Superdex 75 194 3.2/300 PE column (GE Healthcare) eluted in PBS pH 7.4 at 0.8 ml/min using a were loaded in duplicate and analyzed as described previously (Mably et al, 2015).…”

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confidence: 99%

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Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP

et al. 2017

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Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aβ, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aβ depend on expression of APP and that the Aβ-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aβ localizing to synapses and binding of soluble Aβ aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD.SIGNIFICANCE STATEMENTHere, we report on the plasticity-disrupting effects of amyloid β-protein (Aβ) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aβ-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aβ localizing to synapses and genetic ablation of APP prevents both Aβ binding and Aβ-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation.

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“…Aβ species (Mably et al, 2015), samples were analyzed both with and without were diluted 1:10 with assay diluents so that the final GuHCl concentration was 0.5 M.…”

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Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP

et al. 2017

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“…However, one study that administered a total tau antibody to Aβ plaque mice reported treatment induced mortality that should be examined further for that antibody in various tauopathy and wild-type mice [80]. In the clinical trials, there have not been any major side effects reported and those that started first have now advanced to Phase 2.…”

Section: Toxicity Concernsmentioning

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Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

Sigurdsson

2018

JAD

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Tau immunotherapies have now advanced from proof-of-concept studies to Phase 2 clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

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“…Likewise, we have observed mouse death under certain conditions in some animal models which appears to be related to strong immune response to at least some tau immunogens that may be background strain related (unpublished observations). Most recently, enhanced mortality was observed in Aβ plaque mice immunized with a total tau antibody, suggesting that it may be safer to target pathological tau epitopes [29], although that should be studied further in the same model. As detailed above, certain total tau antibodies have successfully cleared tau pathology without reported side effects in models that overexpress the tau protein [14;19].…”

Section: Toxicitymentioning

confidence: 99%

Tau Immunotherapy

Sigurdsson

2015

Neurodegener Dis

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In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-β (Aβ) pathology, greater clinical efficacy may be achieved by clearing tau than Aβ aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.

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Tau immunization: a cautionary tale?

Cited by 28 publications

References 104 publications

Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP

Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

Tau Immunotherapy

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